Gynecologic Oncology 141 (2016) 386401

Contents lists available at ScienceDirect

Gynecologic Oncology
journal homepage: www.elsevier.com/locate/ygyno

Review Article

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer

Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modiers of
BRCA1 and BRCA2, Antoinette Hollestelle a,1, Frederieke H. van der Baan 1,b, Andrew Berchuck c,,1,
Sharon E. Johnatty d, Katja K. Aben e,f, Bjarni A. Agnarsson g,ix, Kristiina Aittomki h, Elisa Alducci i,
Irene L. Andrulis j,k, Hoda Anton-Culver l, Natalia N. Antonenkova m, Antonis C. Antoniou n, Carmel Apicella o,
Volker Arndt p, Norbert Arnold q, Banu K. Arun r,s, Brita Arver t, Alan Ashworth u,
Australian Ovarian Cancer Study Group v,w,x, Laura Baglietto o,y,z, Rosemary Balleine aa, Elisa V. Bandera ab,
Daniel Barrowdale n, Yukie T. Bean ac,ad, Lars Beckmann ae, Matthias W. Beckmann af, Javier Benitez ag,af,ai,
Andreas Berger aj, Raanan Berger ak, Benoit Beuselinck al, Maria Bisogna am, Line Bjorge an,ao, Carl Blomqvist ap,
Natalia V. Bogdanova aq,ar, Anders Bojesen as, Stig E. Bojesen at,au, Manjeet K. Bolla n, Bernardo Bonanni av,
Judith S. Brand aw, Hiltrud Brauch ax,ay,az,iy, Breast Cancer Family Register ba, Hermann Brenner p,
Louise Brinton bb, Angela Brooks-Wilson bc,bd, Fiona Bruinsma o,y,z, Joan Brunet be, Thomas Brning bf,
Agnieszka Budzilowska bg, Clareann H. Bunker bh, Barbara Burwinkel bi,bj, Ralf Butzow bk,bl, Saundra S. Buys bm,
Maria A. Caligo bn, Ian Campbell bo,bp,bq, Jonathan Carter br, Jenny Chang-Claude bs, Stephen J. Chanock bb,
Kathleen B.M. Claes bt, J. Margriet Colle bu, Linda S. Cook bv, Fergus J. Couch bw,bx, Angela Cox by,
Daniel Cramer bz,ca,iz, Simon S. Cross cb, Julie M. Cunningham bx, Cezary Cybulski cc, Kamila Czene aw,
Francesca Damiola cd, Agnieszka Dansonka-Mieszkowska bg, Hatef Darabi aw, Miguel de la Hoya ce,
Anna deFazio x,cf, Joseph Dennis n, Peter Devilee cg,ch, Ed M. Dicks ci, Orland Diez cj, Jennifer A. Doherty ck,
Susan M. Domchek cl,cm, Cecilia M. Doring cn, Thilo Drk aq, Isabel Dos Santos Silva co, Andreas du Bois cp,cq,
Martine Dumont cr, Alison M. Dunning ci, Mercedes Duran cs, Douglas F. Easton n,ci, Diana Eccles ct,
Robert P. Edwards cu, Hans Ehrencrona cv, Bent Ejlertsen cw, Arif B. Ekici cx, Steve D. Ellis n, EMBRACE n,
Christoph Engel cy, Mikael Eriksson aw, Peter A. Fasching af,cz, Lidia Feliubadalo da, Jonine Figueroa bb,
Dieter Flesch-Janys db, Olivia Fletcher u, Annette Fontaine dc,dd, Stefano Fortuzzi de,df, Florentia Fostira dg,
Brooke L. Fridley dh, Tara Friebel di, Eitan Friedman dj,dk, Grace Friel dl, Debra Frost n, Judy Garber dm,
Montserrat Garca-Closas u, Simon A. Gayther dn, GEMO Study Collaborators do,
GENICA Network ax,ay,az,bf,dp,dq,dr,ds,iy, Aleksandra Gentry-Maharaj dt, Anne-Marie Gerdes du, Graham G. Giles o,y,z,
Rosalind Glasspool dv, Gord Glendon dw, Andrew K. Godwin dx, Marc T. Goodman dy, Martin Gore dz,
Mark H. Greene ea, Mervi Grip eb, Jacek Gronwald ec, Daphne Gschwantler Kaulich aj, Pascal Gunel ed,ee,
Starr R. Guzman bw, Lothar Haeberle af, Christopher A. Haiman dn, Per Hall aw, Sandra L. Halverson ef,
Ute Hamann ds, Thomas V.O. Hansen eg, Philipp Harter cp,cq, Jaana M. Hartikainen eh,ei, Sue Healey d, HEBON ej,
Alexander Hein ek, Florian Heitz cp,cq, Brian E. Henderson dn, Josef Herzog dc, Michelle A. T Hildebrandt el,
Claus K. Hgdall em, Estrid Hgdall en,eo, Frans B.L. Hogervorst ep, John L. Hopper o, Keith Humphreys aw,
Tomasz Huzarski ec, Evgeny N. Imyanitov eq, Claudine Isaacs er, Anna Jakubowska ec, Ramunas Janavicius es,
Katarzyna Jaworska ec,et, Allan Jensen en, Uffe Birk Jensen eu, Nichola Johnson u, Arja Jukkola-Vuorinen ev,
Maria Kabisch ds, Beth Y. Karlan ew, Vesa Kataja ei,ex, Noah Kauff ey, KConFab Investigators ez,
Linda E. Kelemen fa,fb,fc, Michael J. Kerin fd, Lambertus A. Kiemeney f,fe, Susanne K. Kjaer em,en, Julia A. Knight ff,fg,
Jacoba P. Knol-Bout b, Irene Konstantopoulou dg, Veli-Matti Kosma eh,ei, Camilla Krakstad an,ao,

Corresponding author at: Duke Cancer Institute, Duke University Medical Center, Box 3079, Durham, NC 27710, USA. Tel.: +1 919 684 4943; fax: +1 919 684 8719.
E-mail address: berch001@mc.duke.edu (A. Berchuck).
1
Equal contributions.

http://dx.doi.org/10.1016/j.ygyno.2015.04.034
0090-8258/ 2015 Elsevier Inc. All rights reserved.

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

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Vessela Kristensen fh,, Karoline B. Kuchenbaecker n, Jolanta Kupryjanczyk bg, Yael Laitman dj,dk,
Diether Lambrechts fj,fk, Sandrina Lambrechts ,fm, Melissa C. Larson fn, Adriana Lasa fo, Pierre Laurent-Puig fp,
Conxi Lazaro da, Nhu D. Le fq, Loic Le Marchand fr, Arto Leminen bl, Jenny Lester ew, Douglas A. Levine am,
Jingmei Li aw, Dong Liang fs, Annika Lindblom ft, Noralane Lindor fu, Jolanta Lissowska fv, Jirong Long ef,
Karen H. Lu fw, Jan Lubinski ec, Lene Lundvall em, Galina Lurie fr, Phuong L. Mai ea, Arto Mannermaa eh,ei,
Sara Margolin fx, Frederique Mariette de,df, Frederik Marme bi,fy, John W.M. Martens a, Leon F.A.G. Massuger fz,
Christine Maugard ga, Sylvie Mazoyer cd, Lesley McGuffog n, Valerie McGuire gb, Catriona McLean gc,
Iain McNeish gd, Alfons Meindl ge, Florence Menegaux ed,ee, Primitiva Menndez gf, Janusz Menkiszak gg,
Usha Menon dt, Arjen R. Mensenkamp gh, Nicola Miller fd, Roger L. Milne o,y, Francesmary Modugno bh,cu,gi,
Marco Montagna i, Kirsten B. Moysich dl, Heiko Mller p, Anna Marie Mulligan gj,gk, Taru A. Muranen bl,
Steven A. Narod gl, Katherine L. Nathanson cl,cm, Roberta B. Ness gm, Susan L. Neuhausen gn, Heli Nevanlinna bl,
Patrick Neven al, Finn C. Nielsen eg, Sune F. Nielsen at,au, Brge G. Nordestgaard at,au, Robert L. Nussbaum go,
Kunle Odunsi dl, Kenneth Oft gp, Edith Olah gq, Olufunmilayo I. Olopade gr, Janet E. Olson bw, Sara H. Olson gs,
Jan C. Oosterwijk gt, Irene Orlow gs, Nick Orr u, Sandra Orsulic ew, Ana Osorio ah,ai,fo, Laura Ottini gu, James Paul dv,
Celeste L. Pearce dn, Inge Sokilde Pedersen gv, Bernard Peissel gw, Tanja Pejovic ac,ad, Liisa M. Pelttari bl,
Jo Perkins n, Jenny Permuth-Wey gx, Paolo Peterlongo de, Julian Peto co, Catherine M. Phelan gx,
Kelly-Anne Phillips o,bp,gy,gz, Marion Piedmonte ha, Malcolm C. Pike dn,gs, Radka Platte n,
Joanna Plisiecka-Halasa bg, Elizabeth M. Poole ca,hb, Bruce Poppe bt, Katri Pylks hc,hd, Paolo Radice he,
Susan J. Ramus dn, Timothy R. Rebbeck cm,hf, Malcolm W.R. Reed by, Gad Rennert hg,hh, Harvey A. Risch hi,
Mark Robson gp, Gustavo C. Rodriguez hj, Atocha Romero ce, Mary Anne Rossing hk,hl, Joseph H. Rothstein gb,
Anja Rudolph bs, Ingo Runnebaum hm, Ritu Salani hn, Helga B. Salvesen an,ao, Elinor J. Sawyer ho,
Joellen M. Schildkraut hp,hq, Marjanka K. Schmidt ep, Rita K. Schmutzler hr,hs, Andreas Schneeweiss bi,fy,
Minouk J. Schoemaker ht, Michael G. Schrauder af, Fredrick Schumacher dn, Ira Schwaab hu, Giulietta Scuvera gw,
Thomas A. Sellers gx, Gianluca Severi o,y,z, Caroline M. Seynaeve a, Mitul Shah ci, Martha Shrubsole ef,
Nadeem Siddiqui hv, Weiva Sieh gb, Jacques Simard cr, Christian F. Singer aj, Olga M. Sinilnikova cd,hw,
Dominiek Smeets fj,fk, Christof Sohn bi, Maria Soller hx, Honglin Song ci, Penny Soucy cr, Melissa C. Southey hy,
Christa Stegmaier hz, Dominique Stoppa-Lyonnet ia,ib,ic, Lara Sucheston dl, SWE-BRCA id, Anthony Swerdlow ht,ie,
Ingvild L. Tangen an,ao, Muy-Kheng Tea aj, Manuel R. Teixeira if,ig, Kathryn L. Terry bz,ca,iz, Mary Beth Terry ih,
Mads Thomassen ii, Pamela J. Thompson dy, Laima Tihomirova ij, Marc Tischkowitz ik, Amanda Ewart Toland il,
Rob A.E.M. Tollenaar im, Ian Tomlinson in,io, Diana Torres ds,ip, Thrse Truong ed,ee, Helen Tsimiklis hy,
Nadine Tung iq, Shelley S. Tworoger ca,hb, Jonathan P. Tyrer ci, Celine M. Vachon bw, Laura J. Van 't Veer ep,
Anne M. van Altena fz, C.J. Van Asperen ir, David van den Berg dn, Ans M.W. van den Ouweland bu,
Helena C. van Doorn is, Els Van Nieuwenhuysen ,fm, Elizabeth J. van Rensburg cn, Ignace Vergote ,fm,
Senno Verhoef ep, Robert A. Vierkant fn, Joseph Vijai ey, Allison F. Vitonis bz,iz, Anna von Wachenfeldt t,
Christine Walsh ew, Qin Wang n, Shan Wang-Gohrke it, Barbara Wappenschmidt hr,hs, Maren Weischer at,au,
Jeffrey N. Weitzel dc, Caroline Weltens al, Nicolas Wentzensen bb, Alice S. Whittemore gb, Lynne R. Wilkens fr,
Robert Winqvist hc,hd, Anna H. Wu dn, Xifeng Wu el, Hannah P. Yang bb, Daniela Zaffaroni gw, M. Pilar Zamora iu,
Wei Zheng ef, Argyrios Ziogas iv, Georgia Chenevix-Trench d, Paul D.P. Pharoah ci,1, Matti A. Rookus iw,1,
Maartje J. Hooning a,1, Ellen L. Goode bw,1
a

Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA
d
Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia
e
Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands
f
Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands
g
Landspitali University Hospital, Reykjavik, Iceland
h
Department of Clinical Genetics, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
i
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
j
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
k
Ontario Cancer Genetics Network, Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
l
Department of Epidemiology, University of California Irvine, Irvine, CA, USA
m
N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
n
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
o
Centre for Epidemiology and Biostatistics, School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia
p
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
q
Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein, University Kiel, Kiel, Germany
r
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
s
Clinical Cancer Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
t
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden
b
c

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u

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Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
Cancer Division, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
w
Peter MacCallum Cancer Institute, Melbourne, VIC, Australia
x
Center for Cancer Research, University of Sydney at Westmead Millennium Institute, Sydney, Australia
y
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia
z
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
aa
Western Sydney and Nepean Blue Mountains Local Health Districts, Westmead Millennium Institute for Medical Research, University of Sydney, Sydney, Australia
ab
Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA
ac
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA
ad
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
ae
Institute for Quality and Efciency in Health Care (IQWiG), Cologne, Germany
af
University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
ag
Centro Nacional de Genotipacin, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
ah
Human Genetics Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
ai
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain
aj
Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
ak
Sheba Medical Center, Tel Aviv, Israel
al
Multidisciplinary Breast Center, University Hospital Leuven, University of Leuven, Belgium
am
Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
an
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
ao
Department of Clinical Science, University of Bergen, Bergen, Norway
ap
Department of Oncology, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
aq
Department of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany
ar
Department of Radiation Oncology, Hannover Medical School, Hannover, Germany
as
Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark
at
Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
au
Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark
av
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan, Italy
aw
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
ax
Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany
ay
University of Tbingen, Tbingen, Germany
az
German Cancer Consortium (DKTK), Heidelberg, Germany
ba
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA, USA
bb
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
bc
Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada
bd
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada
be
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain
bf
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universitt Bochum (IPA), Bochum, Germany
bg
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
bh
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA
bi
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany
bj
Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany
bk
Department of Pathology, Helsinki University Central Hospital, Helsinki, Finland
bl
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
bm
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
bn
Section of Genetic Oncology, Department of Laboratory Medicine, University Hospital of Pisa, University of Pisa, Pisa, Italy
bo
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, Australia
bp
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Australia
bq
Department of Pathology, University of Melbourne, Melbourne, VIC, Australia
br
Gynaecological Oncology, The Chris O'Brien Lifehouse and The University of Sydney, Sydney, Australia
bs
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
bt
Center for Medical Genetics, Ghent University, Ghent, Belgium
bu
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
bv
Division of Epidemiology and Biostatistics, University of New Mexico, Albuquerque, NM, USA
bw
Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
bx
Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Mayo Clinic, Rochester, MN, USA
by
Shefeld Cancer Research Centre, Department of Oncology, University of Shefeld, Shefeld, UK
bz
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA
ca
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
cb
Academic Unit of Pathology, Department of Neuroscience, University of Shefeld, Shefeld, UK
cc
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical Academy, Szczecin, Poland
cd
INSERM U1052, CNRS UMR5286, Universit Lyon 1, Centre de Recherche en Cancrologie de Lyon, Lyon, France
ce
Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain
cf
Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia
cg
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
ch
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
ci
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
cj
Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
ck
Section of Biostatistics and Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA
cl
Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
cm
Basser Research Centre, Abramson Cancer Center, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
cn
Department of Genetics, University of Pretoria, Pretoria, South Africa
co
Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK
cp
Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Klinik Wiesbaden, Wiesbaden, Germany
cq
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany
cr
Centre Hospitalier Universitaire de Qubec Research Center, Laval University, Quebec, Canada
cs
Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain
ct
Faculty of Medicine, University of Southampton, University Hospital Southampton, Southampton, UK
cu
Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Gynecologic Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
cv
Department of Clinical Genetics, Lund University, Lund, Sweden
v

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cw

389

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

Institute of Human Genetics, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany
cy
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
cz
David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, CA, USA
da
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain
db
Department of Cancer Epidemiology/Clinical Cancer Registry, Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany
dc
Clinical Cancer Genetics, City of Hope, Duarte, CA, USA
dd
New Mexico Cancer Center, Albuquerque, NM, USA
de
Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy
df
Cogentech Cancer Genetic Test Laboratory, Milan, Italy
dg
Molecular Diagnostics Laboratory, Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, National Centre for Scientic Research Demokritos, Aghia Paraskevi Attikis,
Athens, Greece
dh
Kansas IDeA Network of Biomedical Research Excellence Bioinformatics Core, The University of Kansas Cancer Center, Kansas City, KS, USA
di
University of Pennsylvania, Philadelphia, PA, USA
dj
The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel
dk
Institute of Oncology, Sheba Medical Center, Tel-Hashomer, Israel
dl
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA
dm
Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA
dn
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
do
GEMO Study: National Cancer Genetics Network, UNICANCER Genetic Group, France
dp
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany
dq
Institute of Pathology, Medical Faculty of the University of Bonn, Bonn, Germany
dr
Institute of Occupational Medicine and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
ds
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
dt
Gynaecological Cancer Research Centre, Department of Women's Cancer, Institute for Women's Health, UCL, London, UK
du
Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
dv
Cancer Research UK Clinical Trials Unit, The Beatson West of Scotland Cancer Centre, Glasgow, UK
dw
Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
dx
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
dy
Samuel Oschin Comprehensive Cancer Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
dz
Gynecological Oncology Unit, The Royal Marsden Hospital, London, UK
ea
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA
eb
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland
ec
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
ed
INSERM U1018, CESP (Center for Research in Epidemiology and Population Health), Environmental Epidemiology of Cancer, Villejuif, France
ee
University Paris-Sud, UMRS 1018, Villejuif, France
ef
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
eg
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
eh
Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland
ei
School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, Biocenter Kuopio, Cancer Center of Eastern Finland, University of Eastern Finland, Kuopio, Finland
ej
The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Coordinating Center: Netherlands Cancer Institute, Amsterdam, The Netherlands
ek
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center, Erlangen, Germany
el
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
em
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
en
Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
eo
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
ep
Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
eq
N.N. Petrov Institute of Oncology, St. Petersburg, Russia
er
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
es
Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, State Research Centre Institute for
Innovative Medicine, Vilnius, Lithuania
et
Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland
eu
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
ev
Department of Oncology, Oulu University Hospital, University of Oulu, Oulu, Finland
ew
Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
ex
Jyvskyl Central Hospital, Jyvskyl, Finland
ey
Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
ez
kConFab: Kathleen Cuningham Consortium for Research into Familial Breast Cancer Peter MacCallum Cancer Center, Melbourne, Australia
fa
Department of Population Health Research, Alberta Health Services-Cancer Care, Calgary, Alberta, Canada
fb
Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada
fc
Department of Oncology, University of Calgary, Calgary, Alberta, Canada
fd
School of Medicine, National University of Ireland, Galway, Ireland
fe
Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands
ff
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
fg
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
fh
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway

Faculty of Medicine (Faculty Division Ahus), Universitetet i Oslo, Norway

fj
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium
fk
Vesalius Research Center (VRC), VIB, Leuven, Belgium

Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium
fm
Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
fn
Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
fo
Genetic and Molecular Epidemiology Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
fp
Universit Paris Sorbonne Cit, UMR-S775 Inserm, Paris, France
fq
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada
fr
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
fs
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA
ft
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
fu
Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, USA
fv
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland
cx

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A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
fy
National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany
fz
Department of Gynecology, Radboud University Medical Centre, Nijmegen, The Netherlands
ga
Laboratoire de Diagnostic Gntique et Service d'Onco-hmatologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hpital Civil, Strasbourg, France
gb
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA
gc
Anatomical Pathology, The Alfred Hospital, Melbourne, Australia
gd
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK
ge
Department of Gynecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany
gf
Servicio de Anatoma Patolgica, Hospital Monte Naranco, Oviedo, Spain
gg
Department of Surgical Gynecology and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland
gh
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
gi
Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
gj
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
gk
Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
gl
Women's College Research Institute, University of Toronto, Toronto, ON, Canada
gm
The University of Texas School of Public Health, Houston, TX, USA
gn
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
go
Department of Medicine and Institute for Human Genetics, University of California, San Francisco, CA, USA
gp
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
gq
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
gr
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, IL, USA
gs
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
gt
University of Groningen, University Medical Center, Department of Genetics, Groningen, The Netherlands
gu
Department of Molecular Medicine, Sapienza University, Rome, Italy
gv
Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
gw
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientico Istituto Nazionale Tumori (INT), Milan, Italy
gx
Department of Cancer Epidemiology, H. Lee Moftt Cancer Center and Research Institute, Tampa, FL, USA
gy
Division of Cancer Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
gz
Department of Medicine, St Vincent's Hospital, The University of Melbourne, Victoria, Australia
ha
NRG Oncology Statistics and Data Management Center, Buffalo, NY, USA
hb
Channing Division of Network Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
hc
Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Genetics, University of Oulu, Oulu University Hospital, Oulu, Finland
hd
Biocenter Oulu, University of Oulu, Oulu, Finland
he
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientico, Istituto Nazionale
Tumori (INT), Milan, Italy
hf
Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
hg
Clalit National Israeli Cancer Control Center, Haifa, Israel
hh
Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Technion, Haifa, Israel
hi
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
hj
NorthShore University Health System, University of Chicago, Evanston, IL, USA
hk
Department of Epidemiology, University of Washington, Seattle, WA, USA
hl
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
hm
Department of Gynecology, Jena University Hospital, Jena, Germany
hn
Ohio State University, Columbus, OH, USA
ho
Division of Cancer Studies, NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London, London, UK
hp
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA
hq
Cancer Prevention, Detection and Control Research Program, Duke Cancer Institute, Durham, NC, USA
hr
Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics, University Hospital of Cologne, Cologne, Germany
hs
Centre for Molecular Medicine Cologne (CMMC), University Hospital of Cologne, Cologne, Germany
ht
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, UK
hu
Institut fr Humangenetik Wiesbaden, Wiesbaden, Germany
hv
Department of Gynecological Oncology, Glasgow Royal Inrmary, Glasgow, UK
hw
Unit Mixte de Gntique Constitutionnelle des Cancers Frquents, Hospices Civils de Lyon, Centre Lon Brard, Lyon, France
hx
Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund, Sweden
hy
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia
hz
Saarland Cancer Registry, Saarbrcken, Germany
ia
Institut Curie, Department of Tumour Biology, Paris, France
ib
Institut Curie, INSERM U830, Paris, France
ic
Universit Paris Descartes, Sorbonne Paris Cit, France
id
Department of Oncology, Lund University, Lund, Sweden
ie
Division of Breast Cancer Research, The Institute of Cancer Research, Sutton, Surrey, UK
if
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
ig
Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal
ih
Department of Epidemiology, Columbia University, New York, NY, USA
ii
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
ij
Latvian Biomedical Research and Study Centre, Riga, Latvia
ik
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada
il
Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University,
Columbus, OH, USA
im
Department of Surgical Oncology, Leiden University Medical Center, Leiden, The Netherlands
in
Welcome Trust Centre for Human Genetics, University of Oxford, UK
io
Oxford Biomedical Research Centre, University of Oxford, UK
ip
Institute of Human Genetics, Ponticia Universidad Javeriana, Bogota, Colombia
iq
Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
ir
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
is
Department of Gynecology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
it
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany
iu
Servicio de Oncologa Mdica, Hospital Universitario La Paz, Madrid, Spain
iv
Department of Epidemiology, Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA
fx

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

iw
ix
iy
iz

391

Division of Molecular Pathology, Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
University of Iceland, School of Medicine, Reykjavik, Iceland
Cancer Research Center (DKFZ), Heidelberg, Germany
Harvard Medical School, Boston, MA, USA

a r t i c l e

i n f o

a b s t r a c t
Objective. Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a
KRAS 3 UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer
risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively
small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
Methods. Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian
Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association
Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modiers of BRCA1 and
BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers).
Results. We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.941.04, p = 0.74) or breast
cancer (OR = 0.98, 95% CI 0.941.01, p = 0.19) and results were consistent among mutation carriers (BRCA1,
ovarian cancer HR = 1.09, 95% CI 0.971.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.971.12, p = 0.27;
BRCA2, ovarian cancer HR = 0.89, 95% CI 0.711.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.941.19, p =
0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR =
0.94, 95% CI 0.831.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.871.06, p = 0.38), and all other
previously-reported associations.
Conclusions. rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for
patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or
management of these cancers.
2015 Elsevier Inc. All rights reserved.

Article history:
Received 9 March 2015
Accepted 19 April 2015
Available online 2 May 2015
Keywords:
KRAS variant
Breast cancer
Ovarian cancer
Genetic association
Clinical outcome

Contents
1.
2.

Introduction . . . . . . . . . . .
Methods . . . . . . . . . . . .
2.1.
Study participants . . . . .
2.2.
Genotyping and imputation
2.3.
Analysis . . . . . . . . .
3.
Results . . . . . . . . . . . . .
4.
Discussion . . . . . . . . . . . .
Conict of interest statement . . . . . .
Acknowledgments . . . . . . . . . . .
Appendix A.
Supplementary data . .
References . . . . . . . . . . . . . .

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1. Introduction
MicroRNAs (miRNAs) are a class of small non-coding RNA molecules
that negatively regulate gene expression by binding partially complementary sites in the 3 untranslated regions (UTRs) of their target
mRNAs. In this way, miRNAs control many cancer-related biological
pathways involved in cell proliferation, differentiation, and apoptosis
[1]. To date, several inherited variants in microRNAs or miRNA target
sites have been reported to confer increased cancer risks [2]. One such
variant is located in the 3 UTR of the KRAS gene (rs61764370 T N G)
for which the rarer G allele has been reported to confer an increased
risk of ovarian, breast, and lung cancer [37] as well as endometriosis
[8], although not consistently [911].
For ovarian cancer, the rs61764370 G allele was also reported to be
associated with increased risk (320 cases, 328 controls). Further increased risks were observed among 23 BRCA1 mutation carriers and
31 women with familial ovarian cancer, but without BRCA1 or BRCA2
mutations [3]. In contrast, no association with ovarian cancer risk was
seen in another, much larger study, based on 8669 cases, 10,012 controls, and 2682 BRCA1 mutation carriers [9]. One criticism on the latter
study was that some of the genotype data were for rs17388148, an
imputed proxy for rs61764370; even though rs17388148 is highly

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391
392
392
393
393
395
395
396
396
396
400

correlated with rs61764370 (r2 = 0.97) and was imputed with high accuracy (r2 = 0.977) [12,13]. The minor allele of rs61764370 was also associated with shorter survival time in a study of 279 ovarian cancer
patients diagnosed after age 52 years with platinum-resistant disease
(28 resistant, 263 not resistant) and with sub-optimal debulking surgery after neoadjuvant chemotherapy (7 sub-optimal, 109 optimal)
[14]. However, another study observed no association between
rs61764370 and ovarian cancer outcome (329 cases) [15].
For breast cancer, a borderline signicant increased frequency of the
rs61764370 G allele was observed in 268 BRCA1 mutation carriers with
breast cancer, but not in 127 estrogen receptor (ER)-negative familial
non-BRCA1/BRCA2 breast cancer patients [5]. However, in a subsequent
study, the variant was reported to be associated with increased risk of
ER/PR negative disease (80 cases, 470 controls), as well as with triple
negative breast cancer diagnosed before age 52 (111 cases, 250 controls),
regardless of BRCA1 mutation status [6]. The validity of these ndings has
been questioned given the very small sample sizes and the number of
subgroups tested [16,17]. Another report found no association with sporadic or familial breast cancer risk (695 combined cases, 270 controls),
but found that the variant was associated with ERBB2-positive and
high grade disease, based on 153 cases who used post-menopausal hormone replacement therapy [18].

392

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

It has also been reported, based on 232 women with both primary
ovarian and breast cancer, that the frequency of the G allele at
rs61764370 was increased for those who were screened negative for
BRCA1 and BRCA2 (92 cases), particularly among those enrolled within
two years of their ovarian cancer diagnosis (to minimize survival bias,
30 cases), those diagnosed with post-menopausal ovarian cancer (63
cases), those with a family history of ovarian or breast cancer (24
cases), and those with a third primary cancer (16 cases) [4].
This notable lack of consistency in ndings between studies might be
expected when appropriate levels of statistical signicance are not used
to declare positive ndings from multiple small subgroup comparisons
or post-hoc hypotheses [19]. In this respect, the dangers of subgroup
analyses in the context of clinical trials are well-recognized [20]. These
are important caveats, particularly since a genetic test for rs61764370
is currently marketed in the US for risk prediction testing to women
who are at increased risk for developing ovarian and/or breast cancer
or women who have been diagnosed with either ovarian or breast cancer
themselves [21]. In general, much larger studies, with sufcient power to

detect positive ndings at much more stringent levels of statistical significance ought to be required to establish the clinical validity of a genetic
test. Therefore, we conducted centralized genotyping of rs61764370
and other variants in the genomic region around the KRAS gene in
140,012 women to examine associations with risk and clinical outcome
of ovarian and breast cancer.
2. Methods
2.1. Study participants
The following three consortia contributed to these analyses: the
Ovarian Cancer Association Consortium (OCAC: 41 studies, Supplementary Table S1) [22], the Breast Cancer Association Consortium (BCAC: 37
studies, Supplementary Table S2) [23], and the Consortium of Modiers
of BRCA1 and BRCA2 (CIMBA: 55 studies, Supplementary Table S3)
[24,25]. OCAC and BCAC consisted of casecontrol studies of unrelated
women, and CIMBA consisted of studies of women with germline

Table 1
Associations between KRAS rs61764370 and risk of ovarian and breast cancer.
For BRCA1 and BRCA2 mutation carrier analyses, cases are affected BRCA1/BRCA2 mutation carriers and controls are unaffected BRCA1/BRCA2 mutation carriers, and relative risks are estimated by hazard ratios; for other analyses, relative risks are estimated by odds ratios; ovarian cancer analyses used OCAC data adjusted for study, age, and the ve European principal
components; breast cancer analyses used BCAC data adjusted for study, age, and the seven European principal components; BRCA1 and BRCA2 mutation carrier analyses used CIMBA data
with age as follow-up time and stratied for country; 95% CI, 95% condence interval.
Number

Ovarian cancer
All invasive
Histology
High-grade serous
Endometrioid
Clear cell
Mucinous
Low-grade serous
First-degree family history
Ovarian cancer
Breast or ovarian cancer
BRCA1/2 mutation negative
BRCA1 mutation carriers
BRCA2 mutation carriers
Enrolled within two years of diagnosis
All invasive
BRCA1 mutation carriers
BRCA2 mutation carriers
Menopausal status
Pre- or peri-menopausal
Post-menopausal
Prior breast cancer
Enrolled within two years of diagnosis
Post-menopausal ovarian cancer
First degree breast or ovarian cancer family history
Breast cancer
All invasive
Receptor status
ER/PR
ER/PR/ERBB2
First-degree family history
Breast cancer
Ovarian or breast cancer
Age diagnosis b52
ER/PR
ER/PR/ERBB2
BRCA1/2 mutation negative
BRCA1 mutation carriers
BRCA2 mutation carriers
Enrolled within two years of diagnosis
All invasive
BRCA1 mutation carriers
BRCA2 mutation carriers
Menopausal status
Pre- or peri-menopausal
Post-menopausal

Minor allele frequency

Relative risk (95% CI)

Cases

Controls

Cases

Controls

p-Value

15,357

30,816

0.0914

0.0949

0.99 (0.941.04)

0.74

6938
2151
1015
1000
485

30,816
30,816
30,816
30,816
30,816

0.0946
0.0834
0.0994
0.0902
0.0705

0.0949
0.0949
0.0949
0.0949
0.0949

1.04 (0.971.11)
0.90 (0.801.00)
1.09 (0.941.27)
0.99 (0.851.16)
0.76 (0.590.97)

0.26
0.06
0.27
0.91
0.03

483
477
346
2332
599

342
18,442
15,492
12,433
7305

0.0803
0.0977
0.1050
0.0954
0.0952

0.0849
0.0915
0.0997
0.0922
0.0966

0.87 (0.601.27)
1.09 (0.931.28)
1.09 (0.851.41)
1.09 (0.971.23)
0.89 (0.711.13)

0.47
0.28
0.49
0.14
0.34

10,121
1095
270

30,815
10,802
6509

0.0942
0.0950
0.0907

0.0949
0.0940
0.0979

0.99 (0.951.04)
1.05 (0.901.23)
0.85 (0.601.20)

0.68
0.52
0.36

4264
11,058

8789
15,903

0.0915
0.0916

0.0927
0.0951

1.02 (0.921.13)
0.99 (0.931.06)

0.68
0.81

426
341
202

30,815
15,903
30,815

0.0943
0.0810
0.0916

0.0949
0.0951
0.0949

0.91 (0.711.17)
0.90 (0.681.21)
0.99 (0.701.40)

0.46
0.49
0.95

33,530

37,640

0.0904

0.0930

0.98 (0.941.01)

0.19

4009
1673

37,043
28,480

0.0940
0.0885

0.0932
0.0947

1.04 (0.961.13)
0.97 (0.851.10)

0.36
0.62

4357
4593

1943
2265

0.0942
0.0933

0.0954
0.0949

0.96 (0.841.10)
0.96 (0.851.09)

0.59
0.52

1530
546
1431
7543
4138

37,043
27,690
1097
7222
3766

0.0980
0.0908
0.0853
0.0935
0.1005

0.0932
0.0948
0.0925
0.0919
0.0921

1.07 (0.951.22)
0.99 (0.811.20)
0.91 (0.751.11)
1.04 (0.971.12)
1.06 (0.941.19)

0.28
0.90
0.35
0.27
0.35

20,444
2595
1359

34,349
5976
3365

0.0924
0.0896
0.0960

0.0934
0.0924
0.0926

0.99 (0.951.04)
0.95 (0.851.05)
1.05 (0.901.23)

0.73
0.30
0.52

7086
16,346

8642
18,605

0.0934
0.0904

0.0933
0.0943

0.98 (0.911.07)
0.98 (0.931.03)

0.70
0.36

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

deleterious BRCA1 or BRCA2 mutations primarily identied through

clinical genetics centers. For the purpose of the current analyses, only
participants of European ancestry were included. Following genotyping,
quality control exclusions (described below), and analysis-specic exclusions, data from the following women were available for analysis:
46,173 OCAC participants (15,357 patients with invasive epithelial
ovarian cancer and 30,816 controls), 71,170 BCAC participants (33,530
patients with invasive breast cancer and 37,640 controls), and 22,669
CIMBA participants (for ovarian cancer analyses: 2332 affected and
12,433 unaffected BRCA1 carriers, 599 affected and 7305 unaffected
BRCA2 carriers; for breast cancer analyses: 7543 affected and 7222
unaffected BRCA1 carriers, 4138 affected and 3766 unaffected BRCA2
carriers). For OCAC, overall and progression-free survival data were
available for 3096 patients from 13 studies. Overall survival data were
available for 28,471 patients from 26 BCAC studies and for 2623
mutation carriers with breast cancer from 11 CIMBA studies (excluding
studies with less than ten deaths) as described previously [26,27]. Each
study was approved by its relevant governing research ethics committee, and all study participants provided written informed consent.

2.2. Genotyping and imputation

Genotyping for rs61764370 was performed using the custom iCOGS
Illumina Innium iSelect BeadChip, as previously described [2225]. In
total, DNA from 185,443 women of varying ethnic background was genotyped (47,630 OCAC participants, 114,255 BCAC participants, 23,558
CIMBA participants), along with HapMap2 DNAs for European, African,
and Asian populations. Genotype data were also available for three
OCAC genome-wide association studies (UK GWAS, US GWAS, Mayo
GWAS) that had been genotyped using either the Illumina
Human610-Quad Beadchip (12,607 participants) [28] or the Illumina
HumanOmni2.5-8 Beadchip (883 participants). Raw intensity data
les underwent centralized genotype calling and quality control
[2225]. HapMap2 samples were used to identify women with predicted European intercontinental ancestry; among these women, a set of
over 37,000 unlinked markers was used to perform principal component (PC) analysis [29]. The rst ve and seven European PCs were
found to control adequately for residual population stratication in
OCAC and BCAC data, respectively. Samples with low conversion rate,
extreme heterozygosity, non-female sex, or one of a rst-degree relative
pair (the latter for OCAC and BCAC only) were excluded. Variants were
excluded if they were monomorphic or had a call rate b 95% (minor allele frequency (MAF) N0.05) or b99% (MAF b 0.05), deviation from
HardyWeinberg equilibrium (p b 107), or N2% duplicate discordance.
In addition to rs61764370, 54 variants within 100 kb on either side
of KRAS on chromosome 12 (25,258,179 to 25,503,854 bp in
GRCh37.p12) were genotyped. Moreover, to provide a common set of
variants across the region for analysis in all the data sets, we also used
imputation to infer genotypes for another 1056 variants and for variants
that failed genotyping. We performed imputation separately for OCAC
samples, BCAC samples, BRCA1 mutation carriers, BRCA2 mutation carriers, and for each of the OCAC GWAS. We imputed variants from the
1000 Genomes Project data using the v3 April 2012 release as the reference panel [30]. To improve computation efciency we initially used a
two-step procedure, which involved pre-phasing using the SHAPEIT
software [31] in the rst step and imputation of the phased data in the
second. We used the IMPUTE version 2 software [32] for the imputation
for all studies with the exception of the US GWAS for which we used the
MACH algorithm implemented in the minimac software version
2012.8.15 and MACH version 1.0.18 [33]. We excluded variants from association analyses if their imputation accuracy was r2 b 0.30 or their
MAF was b0.005, resulting in 974 variants genotyped and imputed for
OCAC, 989 variants genotyped and imputed for BCAC, and 1001 variants
genotyped and imputed for CIMBA, including rs61764370 (Supplementary Tables S5, S6, and S7).

393

2.3. Analysis
Genotypes were coded for genotype dosage as 0, 1, or 2, based on the
number of copies of the minor allele. For ovarian cancer casecontrol
analysis (i.e., OCAC studies), logistic regression provided estimated
risks of invasive epithelial ovarian cancer with odds ratios (ORs) and
95% condence intervals (CIs) adjusting for study, age, and the ve
European PCs. Subgroup analyses were conducted by histology, family
ovarian and breast cancer history, menopausal status, time between
ovarian cancer diagnosis and recruitment, and history of multiple
primary cancers. For breast cancer casecontrol analysis (i.e., BCAC
studies), the association between genotype and invasive breast cancer
risk was evaluated by logistic regression, adjusting for study, age, and
the seven European PCs, providing ORs and 95% CIs. Additional
subgroup analyses were based on receptor status, rst-degree family
ovarian and breast cancer history, BRCA1 and BRCA2 mutation status,
enrollment within two years of diagnosis, menopausal status (i.e. last
menstruation longer than twelve months ago), age at diagnosis less
than 52 years, and history of hormone replacement therapy use (i.e. longer than twelve months use). Risk analysis for BRCA1 and BRCA2 mutation carriers (i.e. CIMBA studies) was done using a Cox proportional
hazard model to estimate hazard ratios (HRs) per copy of the minor allele, with age as follow-up time and stratied by country of residence;
US and Canadian strata were further subdivided by self-reported
Ashkenazi Jewish ancestry [24,25]. A weighted cohort approach was applied to correct for potential testing bias due to overrepresentation of
cases in the study population [34]. We used robust variance estimation
to allow for the non-independence of carriers within the same family
[35]. To assess associations with ovarian cancer risk, mutation carriers
were followed from birth until ovarian cancer diagnosis (event), a
risk-reducing salpingo-oophorectomy (RRSO) or the age at enrollment,
Table 2
Associations between KRAS rs61764370 and outcome in ovarian and breast cancer.
Ovarian cancer analyses used OCAC data adjusted for age at diagnosis (overall survival only), the ve European principal components, histology (serous, mucinous, endometrioid,
clear cell, and other epithelial), grade (low versus high), FIGO stage (IIV), residual disease
after debulking surgery (nil versus any), and stratied by study; breast cancer analyses
used BCAC data adjusted for age at diagnosis, tumor size, nodal status, grade, adjuvant hormonal and/or chemotherapy and was stratied by study; analyses for BRCA1 and BRCA2
mutation carriers used CIMBA data adjusted for age at diagnosis, tumor size, nodal status,
grade, adjuvant hormonal and/or chemotherapy, and preventive bilateral oophorectomy
and was stratied by study; 95% CI, 95% condence interval.
No. of
No. of Hazard ratio
patients events (95% CI)
Ovarian cancer
Overall survival
All patients
Patients who were suboptimally
debulked after cytoreductive
surgery
Post-menopausal patients N 52
years
Progression-free survival
All patients
Patients who were suboptimally
debulked after cytoreductive
surgery
Post-menopausal patients N52

p-Value

3096
1114

1421
784

0.94 (0.831.07) 0.38

0.94 (0.781.13) 0.50

2226

1276

0.97 (0.841.12) 0.70

3096
1114

2144
961

1.01 (0.901.13) 0.84

1.03 (0.871.21) 0.74

2226

1603

1.02 (0.901.16) 0.76

28,471
20,071
4778

3013
1754
771

0.96 (0.871.06) 0.38

0.96 (0.851.10) 0.58
0.97 (0.811.18) 0.78

28,471

1693

0.95 (0.831.08) 0.40

1706
917

241
162

0.72 (0.481.08) 0.11

0.98 (0.651.46) 0.90

years
Breast cancer
Overall survival
All patients
ER-positive patients
ER-negative patients
Breast cancer-specic survival
All patients
Overall survival
BRCA1 mutation carriers
BRCA2 mutation carriers

394

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Fig. 1. Regional association plots for variants within the genomic region 100 kb either side of KRAS and risk of ovarian and breast cancer. X-axis position is referent to position (bp) on
chromosome 12, build GRCh37.p12; yellow line indicates position of KRAS; red triangle indicates rs61764370. Y-axis is log10(p-values) from association tests for risk of A) ER-negative
breast cancer, B) ER-positive breast cancer, C) breast cancer in BRCA1 mutation carriers, D) breast cancer in BRCA2 mutation carriers, E) epithelial ovarian cancer, F) epithelial ovarian cancer in BRCA1 mutation carriers, and G) epithelial ovarian cancer in BRCA2 mutation carriers.

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

whichever occurred rst. We also performed analyses restricted to

women diagnosed or censored within two years before their enrollment. To assess associations with breast cancer risk, mutation carriers
were followed from birth until a breast cancer diagnosis (i.e. either ductal carcinoma in situ or invasive breast cancer), ovarian cancer diagnosis, a risk-reducing bilateral prophylactic mastectomy or the age at
enrollment, whichever occurred rst.
Survival analysis of OCAC patients used Cox proportional hazards
models estimating HRs and 95% CIs considering overall survival as
well as progression-free survival following ovarian cancer diagnosis.
Overall survival was adjusted for age at diagnosis, the ve European
PCs, histology, grade, FIGO stage, and residual disease after debulking
surgery, and stratied by study, left truncating at the date of study
entry and right censoring at ve years to minimize events due to
other causes. Progression-free survival was analyzed as for overall
survival, but without adjustment for age and right censoring, and was
dened as the time between the date of histologic diagnosis and the
rst conrmed sign of disease recurrence or progression, based on
GCIG (Gynecological Cancer InterGroup) criteria [36]. We also performed
subgroup analysis of patients suboptimally debulked after cytoreductive
surgery (residual disease N 1 cm) and of post-menopausal patients (age
at diagnosis N52 years). Survival analysis of BCAC patients used Cox proportional hazard models estimating HRs and 95% CIs considering overall
and breast cancer-specic survival following breast cancer diagnosis.
Models were adjusted for age at diagnosis, tumor size, nodal status,
grade, adjuvant hormonal and/or chemotherapy, and stratied by
study, left-truncating at the date of study entry and right censoring at
ten years. In addition, we performed subgroup analysis on ER-positive
and ER-negative patients. For CIMBA breast cancer patients associations
between genotype and overall survival were evaluated using Cox
proportional hazard models estimating HRs and 95% CIs. Models were
adjusted for age at diagnosis, tumor size, nodal status, grade, adjuvant
hormonal and/or chemotherapy, and preventive bilateral oophorectomy
and stratied by study, left-truncating at the date of study entry and right
censoring at twenty years. Analyses were performed using STATA version 12.0 (StataCorp, Texas, USA).
3. Results
The results of the overall analysis as well as the subgroup analyses
investigating the association between the minor allele at rs61764370
and ovarian cancer risk, breast cancer risk, and ovarian and breast
cancer risks in BRCA1 and BRCA2 mutation carriers are shown in
Table 1. Associations with clinical outcomes in and ovarian and breast
cancer patients including BRCA1 and BRCA2 mutation carriers are
shown in Table 2 and Supplementary Table S4.
We found no evidence for association between the rs61764370 G allele and ovarian or breast cancer risk. The most statistically signicant
association was observed for risk of low-grade serous ovarian cancer
(n = 485; OR 0.76, 95% CI 0.590.97, p = 0.031), but this nding was
not signicant after Bonferroni correction for multiple testing. We also
evaluated the association for additional specic subgroups in which an
association with rs61764370 had been reported previously [36]. Ovarian cancer subgroups considered BRCA1 mutation carriers as well as
BRCA1 and BRCA2 screened-negative patients with rst degree family
histories of breast or ovarian cancer and patients who had been diagnosed with breast cancer before their ovarian cancer diagnoses. For
breast cancer these included, among others, BRCA1 mutation carriers,
patients diagnosed with ER- and PR-negative tumors, and patients
diagnosed with triple negative tumors before age 52 years. Importantly,
we observed no evidence for association of rs61764370 with any of
these subgroups (detailed in Table 1), with all ORs close to unity and
very narrow CIs including unity.
Similarly, case-only analyses did not reveal any associations
between rs61764370 genotype and ovarian and breast cancer clinical
features or outcome (Table 2 and Supplementary Table S4). For

395

example, the previously reported association between rs61764370

and risk of ERBB2-positive and high grade breast cancer in hormone replacement therapy users [18] was not replicated (Supplementary
Table S4), and in ovarian cancer analyses we found no evidence of reduced survival among patients diagnosed after age 52 years or patients
with suboptimal debulking after cytoreductive surgery (Table 2) [14].
The G allele of rs61764370 was also not associated with survival of
breast cancer patients (Table 2).
Finally, we evaluated the association between the primary phenotypes of interest and common genetic variation (MAF N 0.02) in the genomic region of KRAS (i.e., within 100 kb on either side of the gene),
using imputed and genotyped data on 974 variants for OCAC, 989 variants for BCAC, and 1001 variants genotyped and imputed for CIMBA
(Supplementary Tables S5, S6, and S7). We found no evidence of association for any of these variants, including rs61764370 and rs17388148,
with these phenotypes that would withstand Bonferroni correction for
multiple testing, as detailed in Supplementary Tables S5, S6, and S7
and shown in regional association plots (Fig. 1).
4. Discussion
Our analysis of 140,012 women genotyped for inherited variants in
the KRAS region provides denitive clarication of the role of these variants in ovarian and breast cancer susceptibility and outcome. We have
found no evidence to support an association between rs61764370 and
ovarian or breast cancer risk, or clinical outcomes in patients with ovarian or breast cancer. In the absence of any association and with ORs
close to unity we would not typically consider sub-group analyses, particularly sub-groups for which differential associations would not be expected to occur. However, given the previous positive associations
reported for a myriad of different subgroups, we tested for association
among each of these subgroups and found no evidence to support the
previously reported associations.
Our study has notable strengths. The vast majority (i.e. N95%) of the
samples were genotyped using the same genotyping platform and
employing a common approach to genotype calling and quality control;
additional samples used denser arrays and nearly identical procedures.
The very large sample sizes for all the major phenotypes of interest provide substantial statistical power to exclude any clinically relevant associated risks for the major phenotypes of interest (Fig. 2). The null results
found here are thus not due to lack of statistical power, and this analysis
also had greater than 80% power to detect association for most of the
subgroups, although for some subgroups it was not possible to exclude

Fig. 2. Power curve for modest risk variants according to the total sample size. X-axis is
total sample size for which casecontrol ratio is 1:1. Y-axis is the statistical power
(range 0 51 0) for variants given a range of risks, assuming alpha = 0 01 and
minor allele frequency 0 09.

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A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

modest risks. In contrast to the current ndings, other genetic association analyses using the same genotyping platform and the same studies
as included here have identied more than 90 common germline
variants associated with ovarian or breast cancer risk at p b 5 108
[22,23,37]. While critiques on a previous null KRAS report have suggested that inclusion of male controls, use of prevalent cases, and reliance on a surrogate genetic variant may have led to falsely negative
conclusions, these are not issues in the present data set. Rather, we
demonstrate the importance of international collaboration to identify
true associations as well as to refute false associations, an equally important objective.
The rise of individualized medicine including the use of panels of
common variants to predict cancer risk more accurately than using family history alone holds great promise [38]. For example, the 31 prostate
cancer susceptibility alleles conrmed as of 2011 (at p b 5 108) can
be combined to identify men in the top one percent of the risk distribution having a 3.2-fold increased risk [39]. Prediction has since then improved with now over 70 prostate cancer susceptibility alleles [40]
and the utility of these genetic tests is currently under clinical evaluation. A similar clinical examination in ovarian and breast cancer is not
far behind, with now over 18 and 77 conrmed susceptibility alleles, respectively, for these cancers [22,23]. The genotype at rs61764370, however, does not predict ovarian or breast cancer risk, even among
particular subgroups of women or for particular subtypes of disease,
nor is it a marker of differential outcome following diagnosis with
these cancers. Therefore, genetic test results for rs61764370 should
not be used to counsel women about their ovarian or breast cancer
risks or outcome. Our results highlight the dangers of developing clinical
tests without appropriate data from carefully conducted, large-scale
studies to establish clinical validity.
Conict of interest statement
There are no conicts of interest to disclose.
Antoinette Hollestelle and Ellen L. Goode had full access to all of the data in the study and
take responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgments
We thank all the individuals who took part in this study and all the
researchers, clinicians and administrative staff who have made possible
the many studies contributing to this work.
The COGS project is funded through a European Commission's
Seventh Framework Programme grant (agreement number 223175
HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium
is supported by a grant from the Ovarian Cancer Research Fund thanks
to donations by the family and friends of Kathryn Sladek Smith (PPD/
RPCI.07). The scientic development and funding for this project were
in part supported by the US National Cancer Institute GAME-ON PostGWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available
from http://www.wtccc.org.uk/. Funding for the project was provided
by the Wellcome Trust under award 076113.
G.C.-T. and P.M.W. are supported by the National Health and Medical
Research Council; P.A.F. is supported by the Deutsche Krebshilfe; B.K.
holds an American Cancer Society Early Detection Professorship (SIOP06-258-01-COUN); K.-A.P. is an Australian National Breast Cancer Foundation Fellow; and A.B. holds the Barbara Thomason Ovarian Cancer
Research Professorship from the American Cancer Society (SIOP-06090-06). R. Balleine was a Cancer Institute NSW Clinical Research
Fellow.
OCAC, in particular, acknowledges D. Bowtell, A. deFazio, D. Gertig, A.
Green, P. Parsons, N. Hayward and D. Whiteman (AUS); G. Peuteman, T.
Van Brussel and D. Smeets (BEL); U. Eilber and T. Koehler (GER); L.
Gacucova (HMO); P. Schrmann, F. Kramer, W. Zheng, T.-W. ParkSimon, K. Beer-Grondke and D. Schmidt (HJO); Sharon Windebank,

Christopher Hilker and Jason Vollenweider (MAY); the state cancer registries of AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD,
MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA,
and WY (NHS); L. Paddock, M. King, U. Chandran, A. Samoila, and Y.
Bensman (NJO); L. Brinton, M. Sherman, A. Hutchinson, N. SzeszeniaDabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner
(POL); C. Luccarini, P. Harrington, the SEARCH team and ECRIC (SEA);
the Scottish Gynaecological Clinical Trails group and SCOTROC1 investigators (SRO); W-H. Chow and Y-T. Gao (SWH); I. Jacobs, M.
Widschwendter, E. Wozniak, N. Balogun, A. Ryan and J. Ford (UKO);
and Carole Pye (UKR). Funding of the constituent OCAC studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the
California Cancer Research Program (00-01389V-20170, N01CN25403, 2II0200); the Canadian Institutes for Health Research; Cancer
Council Victoria; Cancer Council Queensland; Cancer Council New South
Wales; Cancer Council South Australia; Cancer Council Tasmania;
Cancer Foundation of Western Australia; the Cancer Institute of New
Jersey; Cancer Research UK (C490/A6187, C490/A10119, C490/
A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer
Foundation the Danish Cancer Society (94-222-52); ELAN Funds of the
University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki
University Central Hospital Research Fund; Imperial Experimental
Cancer Research Centre (C1312/A15589); the Ovarian Cancer Research
Fund; Nationaal Kankerplan of Belgium; the L & S Milken Foundation;
the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2
PO5A 068 27); the Roswell Park Cancer Institute Alliance Foundation;
the US National Cancer Institute (K07-CA095666, K07-CA143047,
K22-CA138563, N01-CN55424, N01-PC067010, N01-PC035137,
P01-CA017054, P01-CA087696, P30-CA15083, P50-CA105009, P50CA136393, R01-CA014089, R01-CA016056, R01-CA017054, R01CA049449, R01-CA050385, R01-CA054419, R01-CA058598, R01CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01CA076016, R01-CA080978, R01-CA087538, R01-CA092044, R01095023, R01-CA106414, R01-CA122443, R01-CA112523, R01CA114343, R01-CA126841, R01-CA149429, R01CA83918, R03CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01CA069417, U01-CA071966 and Intramural research funds); the US
Army Medical Research and Material Command (DAMD17-98-18659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-10669, W81XWH-07-0449); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of
Clinical Biomedical Research (01 GB 9401); the state of BadenWrttemberg through Medical Faculty of the University of Ulm
(P.685); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V.
Smith Foundation (LVS-39420); the Oak Foundation; the OHSU
Foundation; the Mermaid I project; the Rudolf-Bartling Foundation;
the UK National Institute for Health Research Biomedical Research
Centres at the University of Cambridge, Imperial College London,
University College Hospital Women's Health Theme and the
Royal Marsden Hospital; and WorkSafeBC.
CIMBA studies also acknowledge the following. BCFR: This work was
supported by grant UM1 CA164920 from the National Cancer Institute.
The content of this manuscript does not necessarily reect the views
or policies of the National Cancer Institute or any of the collaborating
centers in the Breast Cancer Family Registry (BCFR), nor does mention
of trade names and commercial products, or organizations imply endorsement by the US Government or the BCFR. BCFR-AU: Maggie
Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR-NY: We
wish to thank members and participants in the New York site of the
Breast Cancer Family Registry for their contributions to the study.
BCFR-ON: We wish to thank members and participants in the Ontario
Familial Breast Cancer Registry for their contributions to the study.
BFBOCC: BFBOCC is partly supported by: Lithuania (BFBOCC-LT):

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Research Council of Lithuania grant LIG-07/2012; Latvia (BFBOCC-LV) is

partly supported by LSC grant 10.0010.08 and in part by a grant from the
ESF Nr.2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 and Liepaja's municipal council. BFBOCC-LT: we acknowledge Vilius Rudaitis, Laimonas
Grikeviius, Ramnas Janaviius (if not in the authorship). BFBOCCLV acknowledges Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics.
BIDMC: BIDMC is supported by the Breast Cancer Research Foundation.
BMBSA: BRCA-gene mutations and breast cancer in South African
women (BMBSA) was supported by grants from the Cancer Association
of South Africa (CANSA) to Elizabeth J. van Rensburg. BMBSA: We wish
to thank the families who contribute to the BMBSA study. BRICOH: SLN
was partially supported by the Morris and Horowitz Familes Endowed
Professorship. We wish to thank Yuan Chun Ding and Linda Steele for
their work in participant enrollment and biospecimen and data management. CBCS: This work was supported by the NEYE Foundation.
CNIO: This work was partially supported by Spanish Association against
Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilea
Foundation (FMMA) and SAF2010-20493. We thank Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. COH-CCGCRN: City
of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number
RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and
the Ofce of the Director, National Institutes of Health. The content is
solely the responsibility of the authors and does not necessarily represent the ofcial views of the National Institutes of Health. CONSIT
TEAM: Italian Association for Cancer Research (AIRC) and funds from
Italian citizens who allocated the 5 1000 share of their tax payment
in support of the Fondazione IRCCS Istituto Nazionale Tumori, according
to Italian laws (INT-Institutional strategic projects 5 1000). CORE:
The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. SH is
supported by an NHMRC Program Grant ot GCT. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior
Principal Research Fellow. DEMOKRITOS: This research has been conanced by the European Union (European Social Fund ESF) and
Greek national funds through the Operational Program Education and
Lifelong Learning of the National Strategic Reference Framework
(NSRF) Research Funding Program of the General Secretariat for Research & Technology: ARISTEIA. Investing in knowledge society through
the European Social Fund. DKFZ: The DKFZ study was supported by the
DKFZ. EMBRACE: EMBRACE is supported by Cancer Research UK Grants
C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are
supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The
Royal Marsden NHS Foundation Trust are supported by an NIHR grant
to the Biomedical Research Centre at The Institute of Cancer Research
and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth
Bancroft are supported by Cancer Research UK Grant C5047/A8385. Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE):
Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centres
are: Coordinating Centre, Cambridge: Debra Frost, Steve Ellis, Elena
Fineberg, Radka Platte. North of Scotland Regional Genetics Service,
Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland
Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West
Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole,
Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service,
Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics
Service, Cambridge: Marc Tischkowitz, Joan Paterson, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T.
Rogers, Emma McCann. St James's Hospital, Dublin & National Centre
for Medical Genetics, Dublin: M. John Kennedy, David Barton. South
East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous,
Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole
Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill.
West of Scotland Regional Genetics Service, Glasgow: Rosemarie
Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark

397

Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias,

Alexis Duncan. South East Thames Regional Genetics Service, Guy's Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman. North West
Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire
Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional
Genetics Service, Leeds: Julian Adlard, Gemma Serra-Feliu. Cheshire &
Merseyside Clinical Genetics Service, Liverpool: Ian Ellis, Catherine
Houghton. Manchester Regional Genetics Service, Manchester: D
Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional
Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl
Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline
Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle:
Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics
Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Halliday, Sarah
Durell, Barbara Stayner. The Institute of Cancer Research and Royal
Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen
Rahman, Richard Houlston, Elizabeth Bancroft, Elizabeth Page, Audrey
Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Emma Killick,
Sue Martin, Gillian Rea, Anjana Kulkarni. North Trent Clinical Genetics
Service, Shefeld: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South
West Thames Regional Genetics Service, London: Shirley Hodgson,
Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha
Tripathi, Virginia Attard, Anna Lehmann. Wessex Clinical Genetics
Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke
Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. FCCC: The
authors acknowledge support from The University of Kansas Cancer
Center (P30 CA168524) and the Kansas Bioscience Authority Eminent
Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323,
and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. We thank Ms. JoEllen Weaver and Dr. Betsy Bove for their
technical support. GC-HBOC: The German Consortium of Hereditary
Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 109076, Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC). GEMO: The study was supported by
the Ligue National Contre le Cancer; the Association Le cancer du sein,
parlons-en! Award; and the Canadian Institutes of Health Research for
the CIHR Team in Familial Risks of Breast Cancer program. Genetic
Modiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study:
National Cancer Genetics Network UNICANCER Genetic Group,
France. We wish to thank all the GEMO collaborating groups for their
contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unit Mixte de Gntique Constitutionnelle des Cancers
Frquents, Hospices Civils de Lyon Centre Lon Brard, & Equipe
Gntique du cancer du sein, Centre de Recherche en Cancrologie
de Lyon: Olga Sinilnikova, Sylvie Mazoyer, Francesca Damiola, Laure
Barjhoux, Carole Verny-Pierre, Alain Calender, Sophie Giraud, Mlanie
Lone; and Service de Gntique Oncologique, Institut Curie, Paris:
Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher,
Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo,
Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressacde-Paillerets, Olivier Caron. Centre Jean Perrin, ClermontFerrand:
Yves-Jean Bignon, Nancy Uhrhammer. Centre Lon Brard, Lyon:
Christine Lasset, Valrie Bonadona, Sandrine Handallou. Centre Franois
Baclesse, Caen: Agns Hardouin, Pascaline Berthet. Institut Paoli
Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi,
Audrey Remenieras, Franois Eisinger. CHU Arnaud-de-Villeneuve,
Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille:
Jean-Philippe Peyrat, Jolle Fournier, Franoise Rvillion, Philippe
Vennin, Claude Adenis. Hpital Ren Huguenin/Institut Curie, St
Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine
Nogues. Centre Paul Strauss, Strasbourg: Danile Muller, Jean-Pierre
Fricker. Institut Bergoni, Bordeaux: Emmanuelle Barouk-Simonet,
Franoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy.
Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud,
Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux,
Hlne Dreyfus, Christine Rebischung, Magalie Peysselon. CHU Dijon:

398

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Fanny Coron, Laurence Faivre. CHU St-Etienne: Fabienne Prieur, Marine

Lebrun, Caroline Kientz. Htel Dieu Centre Hospitalier, Chambry:
Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frnay. CHU
Limoges: Laurence Vnat-Bouvet. CHU Nantes: Capucine Delnatte.
CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier
Piti-Salptrire, Paris: Florence Coulet, Chrystelle Colas, Florent
Soubrier. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam
Bronner. CHU Besanon: Marie-Agns Collonge-Rame, Alexandre
Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L.
Snyder. G-FAST: Bruce Poppe is a senior clinical investigator for the
Fund for Scientic Research Flanders (FWO). We wish to thank the technical support of Ilse Coene en Brecht Crombez. GOG: This study was supported by National Cancer Institute grants to the Gynecologic Oncology
Group (GOG) Administrative Ofce and Tissue Bank (CA 27469), the
GOG Statistical and Data Center (CA 37517), and GOG's Cancer Prevention and Control Committee (CA 101165). Drs. Greene, Mai and Savage
were supported by funding from the Intramural Research Program, NCI.
HCSC: Was supported by a grant RD12/00369/0006 and 12/00539 from
ISCIII (Spain), partially supported by European Regional Development
FEDER funds. We acknowledge Alicia Tosar for her technical assistance.
HEBCS: The HEBCS was nancially supported by the Helsinki University
Central Hospital Research Fund, Academy of Finland (132473), the
Finnish Cancer Society and the Sigrid Juselius Foundation. HEBCS
would like to thank Karl von Smitten, Tuomas Heikkinen, Dario Greco,
and Irja Erkkil. HEBON: The HEBON study is supported by the Dutch
Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756,
the NWO grant 91109024, the Pink Ribbon grant 110005 and the
BBMRI grant CP46/NWO. HEBON stands for The Hereditary Breast and
Ovarian Cancer Research Group Netherlands and consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van
Leeuwen, S. Verhoef, M.K. Schmidt, J.L. de Lange; Erasmus Medical Center, Rotterdam, NL: J.M. Colle, A.M.W. van den Ouweland, M.J. Hooning,
C. Seynaeve, C.H.M. van Deurzen; Leiden University Medical Center, NL:
C.J. van Asperen, J.T. Wijnen, R.A. Tollenaar, P. Devilee, T.C.T.E.F. van
Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M.
Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL:
M.G.E.M. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL:
C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam,
NL: J.J.P. Gille, Q. Waissz, H.E.J. Meijers-Heijboer; University Hospital
Maastricht, NL: E.B. Gmez-Garcia, M.J. Blok; University Medical Center
Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de
Bock. The Netherlands Foundation for the detection of hereditary tumors, Leiden, NL: H.F. Vasen. HUNBOCS: Hungarian Breast and Ovarian
Cancer Study was supported by Hungarian Research Grant KTIA-OTKA
CK-80745. We wish to thank to Hungarian Breast and Ovarian Cancer
Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Judit
Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department
of Molecular Genetics, National Institute of Oncology, Budapest,
Hungary) and the clinicians and patients for their contributions to this
study. ICO: Contract grant sponsor: Asociacin Espaola Contra el Cncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan
Health Institute and Autonomous Government of Catalonia. Contract
grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/
01422, PI10/00748, PI13/00285 and 2009SGR290. We wish to thank
the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella
and all ICO study participants, clinicians, family doctors, researchers
and technicians for their contributions and commitment to this study.
IHCC: Katarzyna Jaworska is a fellow of International PhD program,
Postgraduate School of Molecular Medicine, Warsaw Medical University, supported by the Polish Foundation of Science. ILUH: The ILUH group
was supported by the Icelandic Association Walking for Breast Cancer
Research and by the Landspitali University Hospital Research Fund.
INHERIT: This work was supported by the Canadian Institutes of Health
Research for the CIHR Team in Familial Risks of Breast Cancer program, the Canadian Breast Cancer Research Alliance-grant #019511

and the Ministry of Economic Development, Innovation and Export

Trade grant # PSR-SIIRI-701. We would like to thank Dr Martine
Dumont, Martine Tranchant for sample management and skillful technical assistance. J.S. is Chairholder of the Canada Research Chair in
Oncogenetics. IOVHBOCS: The study was supported by Ministero della
Salute and 5 1000 Istituto Oncologico Veneto grant. KCONFAB:
kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC)
and by the Queensland Cancer Fund, the Cancer Councils of New
South Wales, Victoria, Tasmania and South Australia, and the Cancer
Foundation of Western Australia. GCT and ABS is an NHMRC Senior Research Fellow. We wish to thank Heather Thorne, Eveline Niedermayr,
all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded 20012009
by NHMRC and currently by the National Breast Cancer Foundation and
Cancer Australia #628333) for their contributions to this resource, and
the many families who contribute to kConFab. MAYO: MAYO is supported by NIH grant CA128978, an NCI Specialized Program of Research
Excellence (SPORE) in Breast Cancer (CA116201), a U.S. Department
of Defence Ovarian Cancer Idea award (W81XWH-10-1-0341) and a
grant from the Breast Cancer Research Foundation. MCGILL: Jewish
General Hospital Weekend to End Breast Cancer, Quebec Ministry of
Economic Development, Innovation and Export Trade. MODSQUAD:
The work was supported by the European Regional Development
Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/
2.1.00/03.0101) and MH CZ DRO (MMCI, 00209805). MSKCC:
MSKCC is supported by Breast Cancer Research Foundation, the Niehaus
Family Genetics Research Fund and the STARR Cancer Consortium
Grants. NAROD: 1R01 CA149429-01. NCI: The research of Drs. MH
Greene, PL Mai and SA Savage was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support
services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat,
Inc., Rockville, MD. NICCC: NICCC is supported by Clalit Health Services
in Israel. Some of its activities are supported by the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. We wish
to thank the NICCC National Familial Cancer Consultation Service team
led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research eld operations team led by Dr. Mila Pinchev. NNPIO: This work
has been supported by the Russian Federation for Basic Research (grants
11-04-00227, 12-04-00928 and 12-04-01490) and the Federal Agency
for Science and Innovations, Russia (contract 02.740.11.0780). OSU
CCG: OSUCCG is supported by the Ohio State University Comprehensive
Cancer Center. Leigha Senter, Kevin Sweet, Caroline Craven and
Michelle O'Connor were instrumental in accrual of study participants,
ascertainment of medical records and database management. Samples
were processed by the OSU Human Genetics Sample Bank. PBCS: This
work was supported by the ITT (Istituto Toscano Tumori) grants
20112013. SMC: This project was partially funded through a grant by
the Israel cancer association and the funding for the Israeli Inherited
breast cancer consortium. SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the
Sheba Medical Center for assistance in this study. SWE-BRCA: SWEBRCA collaborators are supported by the Swedish Cancer Society. Swedish scientists participating as SWE-BRCA collaborators are: from Lund
University and University Hospital: ke Borg, Hkan Olsson, Helena
Jernstrm, Karin Henriksson, Katja Harbst, Maria Soller, Niklas Loman,
Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital:
Anna fverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi;
from Stockholm and Karolinska University Hospital: Anna von
Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela
Barbany Bustinza, Johanna Rantala; from Ume University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson;
from Uppsala University: Hans Ehrencrona, Maritta Hellstrm Pigg,
Richard Rosenquist; and from Linkping University Hospital: Marie
Stenmark-Askmalm, Sigrun Liedgren. UCHICAGO: UCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Breast Cancer (CA125183), R01 CA142996, U01 CA161032 and by the

Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast
Cancer research Foundation. OIO is an ACS Clinical Research Professor.
We wish to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our
program. UCLA: Patricia Ganz and the Jonsson Comprehensive Cancer
Center Foundation; Breast Cancer Research Foundation. We thank
Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for
this study. UCSF: UCSF Cancer Risk Program and Helen Diller Family
Comprehensive Cancer Center. We would like to thank Dr. Robert
Nussbaum and the following genetic counselors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin
Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for
her data management. UKFOCR: UKFOCR was supported by a project
grant from CRUK to Paul Pharoah. We thank Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR.
UPENN: National Institutes of Health (NIH) (R01-CA102776 and
R01-CA083855); Breast Cancer Research Foundation; Rooney Family
Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. VFCTG: Victorian Cancer Agency, Cancer
Australia, National Breast Cancer Foundation. Geoffrey Lindeman,
Marion Harris, and Martin Delatycki of the Victorian Familial Cancer
Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplication. WCP: The Women's Cancer Program (WCP) at the Samuel
Oschin Comprehensive Cancer Institute is funded by the American
Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN).
BCAC studies also acknowledge the following. We thank all the individuals who took part in these studies and all the researchers, clinicians,
technicians and administrative staff who have enabled this work to be
carried out. Part of this work was supported by the European
Community's Seventh Framework Programme under grant agreement
number 223175 (grant number HEALTH-F2-2009-223175) (COGS).
This work was partly supported by the Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program
(J.S. & D.E.), and the Ministry of Economic Development, Innovation
and Export Trade of Quebec grant # PSR-SIIRI-701 (J.S. & D.E., P.
Hall). The BCAC is funded by CR-UK (C1287/A10118 and C1287/
A12014). Meetings of the BCAC have been funded by the European
Union COST program (BM0606). D.F.E. is a Principal Research Fellow
of CR-UK. J.S. is chair holder of the Canada Research Chair in
Oncogenetics. ABCFS: Maggie Angelakos, Judi Maskiell, and Gillian
Dite. The ABCFS, NC-BCFR and OFBCR work was supported by the
United States National Cancer Institute, National Institutes of Health
(NIH) under RFA-CA-06-503 and through cooperative agreements
with members of the Breast Cancer Family Registry (BCFR) and Principal
Investigators, including Cancer Care Ontario (U01 CA69467), Northern
California Cancer Center (U01 CA69417), and University of Melbourne
(U01 CA69638). Samples from the NC-BCFR were processed and distributed by the Coriell Institute for Medical Research. The content of this
manuscript does not necessarily reect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR,
nor does mention of trade names and commercial products, or organizations imply endorsement by the US Government or the BCFR. The
ABCFS was also supported by the National Health and Medical Research
Council of Australia, the New South Wales Cancer Council, the Victorian
Health Promotion Foundation (Australia) and the Victorian Breast Cancer Research Consortium. J.L.H. is a National Health and Medical Research Council (NHMRC) Australia Fellow and a Victorian Breast
Cancer Research Consortium Group Leader. M.C.S. is a NHMRC Senior
Research Fellow and a Victorian Breast Cancer Research Consortium
Group Leader. The ABCS study was supported by the Dutch Cancer Society [grants NKI 2007-3839; 2009 4363]; BBMRI-NL, which is a Research
Infrastructure nanced by the Dutch government (NWO 184.021.007);

399

and the Dutch National Genomics Initiative. BBCC: The work of the BBCC
was partly funded by ELAN-Fond of the University Hospital of Erlangen.
BBCS: Eileen Williams, Elaine Ryder-Mills, Kara Sargus. The BBCS is
funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and
the National Cancer Research Network (NCRN). BIGGS: ES is supported
by NIHR Comprehensive Biomedical Research Centre, Guy's & St. Thomas'
NHS Foundation Trust in partnership with King's College London, United
Kingdom. IT is supported by the Oxford Biomedical Research Centre. Niall
McInerney, Gabrielle Colleran, Andrew Rowan, Angela Jones. BSUCH: The
BSUCH study was supported by the Dietmar-Hopp Foundation, the
Helmholtz Society and the German Cancer Research Center (DKFZ).
Peter Bugert, Medical Faculty Mannheim. CECILE: The CECILE study was
funded by Fondation de France, Institut National du Cancer (INCa),
Ligue Nationale contre le Cancer, Ligue contre le Cancer Grand Ouest,
Agence Nationale de Scurit Sanitaire (ANSES), and Agence Nationale
de la Recherche (ANR). CNIO-BCS: The CNIO-BCS was supported by
the Genome Spain Foundation, the Red Temtica de Investigacin
Cooperativa en Cncer and grants from the Asociacin Espaola Contra
el Cncer and the Fondo de Investigacin Sanitario (PI11/00923 and
PI081120). The Human Genotyping-CEGEN Unit (CNIO) is supported by
the Instituto de Salud Carlos III. Guillermo Pita, Charo Alonso, Daniel
Herrero, Nuria lvarez, Pilar Zamora, Primitiva Menendez, the Human
Genotyping-CEGEN Unit (CNIO). CTS: The CTS was supported by the
California Breast Cancer Act of 1993; National Institutes of Health (grants
R01 CA77398 and the Lon V Smith Foundation [LVS39420]); and the
California Breast Cancer Research Fund (contract 97-10500). Collection
of cancer incidence data used in this study was supported by the
California Department of Public Health as part of the statewide cancer
reporting program mandated by California Health and Safety Code
Section 103885. ESTHER: The ESTHER study was supported by a grant
from the Baden Wrttemberg Ministry of Science, Research and Arts. Additional cases were recruited in the context of the VERDI study, which
was supported by a grant from the German Cancer Aid (Deutsche
Krebshilfe). Hartwig Ziegler, Sonja Wolf, Volker Hermann. GENICA: The
GENICA was funded by the Federal Ministry of Education and Research
(BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0 and
01KW0114, the Robert Bosch Foundation, Stuttgart, Deutsches
Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention
and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), as well as the Department of
Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter
Krankenhaus, Bonn, Germany. The GENICA Network: Dr. Margarete
Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tbingen, Germany; [H.B., Wing-Yee Lo, Christina Justenhoven], Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH,
Johanniter Krankenhaus, Bonn, Germany [Yon-Dschun Ko, Christian
Baisch], Institute of Pathology, University of Bonn, Bonn, Germany
[Hans-Peter Fischer], Molecular Genetics of Breast Cancer, Deutsches
Krebsforschungszentrum (DKFZ), Heidelberg, Germany [U.H.], Institute
for Prevention and Occupational Medicine of the German Social Accident
Insurance, Institute of the Ruhr University Bochum (IPA), Germany [T.B.,
Beate Pesch, Sylvia Rabstein, Anne Spickenheuer], Institute of Occupational Medicine and Maritime Medicine, University Medical Center
Hamburg-Eppendorf, Germany [Volker Harth]. HEBCS: The HEBCS was nancially supported by the Helsinki University Central Hospital Research
Fund, Academy of Finland (132473), the Finnish Cancer Society, The
Nordic Cancer Union and the Sigrid Juselius Foundation. Karl von Smitten,
Tuomas Heikkinen, Dario Greco, Irja Erkkil. HMBCS: The HMBCS was
supported by a grant from the Friends of Hannover Medical School and
by the Rudolf Bartling Foundation. Peter Hillemanns, Hans Christiansen
and Johann H. Karstens. HUBCS: The HUBCS was supported by a grant
from the German Federal Ministry of Research and Education (RUS08/
017). KARBAC: The KARBAC study was supported by the Swedish Cancer
Society, the Gustav V Jubilee Foundation and the Bert von Kantzow foundation. KBCP: The KBCP was nancially supported by the special

400

A. Hollestelle et al. / Gynecologic Oncology 141 (2016) 386401

Government Funding (EVO) of Kuopio University Hospital grants, Cancer

Fund of North Savo, the Finnish Cancer Organizations, the Academy of
Finland and by the strategic funding of the University of Eastern
Finland. Eija Myhnen, Helena Kemilinen. kConFab/AOCS: kConFab is
supported by grants from the National Breast Cancer Foundation, the
NHMRC, the Queensland Cancer Fund, the Cancer Councils of New
South Wales, Victoria, Tasmania and South Australia and the Cancer
Foundation of Western Australia. The kConFab Clinical Follow Up Study
was funded by the NHMRC [145684, 288704, 454508]. Financial support
for the AOCS was provided by the United States Army Medical Research
and Materiel Command [DAMD17-01-1-0729], Cancer Council Victoria,
Queensland Cancer Fund, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, Cancer
Council Tasmania and the National Health and Medical Research Council
of Australia [NHMRC; 400413, 400281,199600]. G.C.T. and P.W. are supported by the NHMRC. Heather Thorne, Eveline Niedermayr, the AOCS
Management Group (D Bowtell, G Chenevix-Trench, A deFazio, D Gertig,
A Green, P Webb), the ACS Management Group (A Green, P Parsons, N
Hayward, P Webb, D Whiteman). LMBC: LMBC is supported by the
Stichting tegen Kanker (232-2008 and 196-2010). Diether Lambrechts
is supported by the FWO and the KULPFV/10/016-SymBioSysII. Gilian
Peuteman, Dominiek Smeets, Thomas Van Brussel and Kathleen
Corthouts. MARIE: The MARIE study was supported by the Deutsche
Krebshilfe e.V. [70-2892-BR I], the Hamburg Cancer Society, the German
Cancer Research Center and the genotype work in part by the Federal
Ministry of Education and Research (BMBF) Germany [01KH0402].
Tracy Slanger, Elke Mutschelknauss, Ramona Salazar, S. Behrens, R. Birr,
W. Busch, U. Eilber, B. Kaspereit, N. Knese, K. Smit. MBCSG: MBCSG was
funded by grants from the Italian Association for Cancer Research
(AIRC) and thanks Siranoush Manoukian of the Istituto Nazionale dei
Tumori, Milano, Italy; Monica Barile and Irene Feroce of the Istituto
Europeo di Oncologia, Milan, Italy; Giuseppe Giannini of the Sapienza
University, Rome, Italy; Loris Bernard end per personnel of the Cogentech
Cancer Genetic Test Laboratory, Milan, Italy. MCBCS: The MCBCS was
supported by the NIH grants [CA122340, CA128978], an NIH Specialized
Program of Research Excellence (SPORE) in Breast Cancer [CA116201],
the Breast Cancer Research Foundation, and the Komen Race for the
Cure. MCCS: MCCS cohort recruitment in the study was funded by
VicHealth and Cancer Council Victoria. The MCCS was further supported
by Australian NHMRC grants 209057, 251553 and 504711 and by
infrastructure provided by Cancer Council Victoria. MEC: The MEC was
support by NIH grants CA63464, CA54281, CA098758 and CA132839.
MTLGEBCS: The authors gratefully acknowledge Martine Tranchant
for DNA extraction, sample management and skillful technical assistance.
J.S. is Chairholder of the Canada Research Chair in Oncogenetics. The
work of MTLGEBCS was supported by the Canadian Institutes of
Health Research for the CIHR Team in Familial Risks of Breast Cancer
program grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade grant # PSR-SIIRI-701. NBCS: The
NBCS was supported by grants from the Norwegian Research council,
155218/V40, 175240/S10 to ALBD, FUGE-NFR 181600/V11 to VNK and
a Swizz Bridge Award to ALBD. NBHS: The NBHS was supported by NIH
grant R01CA100374. Biological sample preparation was conducted the
Survey and Biospecimen Shared Resource, which is supported by P30
CA68485. We thank study participants and research staff for their contributions and commitment to this study. NHS: The NHS was funded by NIH
grant CA87969. OBCS: The OBCS was supported by research grants from
the Finnish Cancer Foundation, the Academy of Finland, the University of
Oulu, and the Oulu University Hospital. Meeri Otsukka, Kari Mononen.
OFBCR: Teresa Selander, Nayana Weerasooriya. ORIGO: The ORIGO
study was supported by the Dutch Cancer Society (RUL 1997-1505) and
the Biobanking and Biomolecular Resources Research Infrastructure
(BBMRI-NL CP16). We thank E. Krol-Warmerdam, and J. Blom for patient
accrual, administering questionnaires, and managing clinical information.
The LUMC survival data were retrieved from the Leiden hospital-based
cancer registry system (ONCDOC) with the help of Dr. J. Molenaar.

PBCS: The PBCS was funded by Intramural Research Funds of the National
Cancer Institute, Department of Health and Human Services, USA. Louise
Brinton, Mark Sherman, Stephen Chanock, Neonila SzeszeniaDabrowska, Beata Peplonska, Witold Zatonski, Pei Chao, Michael Stagner.
pKARMA: The pKARMA study was supported by Mrit and Hans Rausings
Initiative Against Breast Cancer. The Swedish Medical Research Counsel.
RBCS: The RBCS was funded by the Dutch Cancer Society (DDHK 20043124, DDHK 2009-4318). Petra Bos, Jannet Blom, Ellen Crepin, Elisabeth
Huijskens, Annette Heemskerk, the Erasmus MC Family Cancer Clinic.
SASBAC: The SASBAC study was supported by funding from the Agency
for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer
Foundation. The Swedish Medical Research Counsel. SBCS: The SBCS
was supported by Yorkshire Cancer Research S295, S299, S305PA. Sue
Higham, Helen Cramp, and Dan Connley. SEARCH: SEARCH is funded by
program grants from Cancer Research UK [C490/A11021 and C490/
A10124]. The SEARCH and EPIC teams. SKKDKFZS: SKKDKFZS is supported by the DKFZ. We thank all study participants, clinicians, family doctors,
researchers and technicians for their contributions and commitment to
this study. SZBCS: The SZBCS was supported by Grant PBZ_KBN_122/
P05/2004; Katarzyna Jaworska is a fellow of International PhD program,
Postgraduate School of Molecular Medicine, Warsaw Medical University,
supported by the Polish Foundation of Science. UKBGS: The UKBGS is
funded by Breakthrough Breast Cancer and the Institute of Cancer
Research (ICR). ICR acknowledges NHS funding to the NIHR Biomedical
Research Centre. We thank Breakthrough Breast Cancer and the Institute
of Cancer Research for support and funding of the Breakthrough Generations Study, and the study participants, study staff, and the doctors,
nurses and other health care providers and health information sources
who have contributed to the study. Genome Quebec: The authors
would like to acknowledge the contribution of the staff of the genotyping
unit under the supervision of Dr. Sylvie LaBoissire as well as Frdrick
Robidoux from the McGill University and Gnome Qubec Innovation
Centre.
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.ygyno.2015.04.034.
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