- Detroit, United States
Zeng-Quan Yang
Wayne State University, Oncology, Faculty Member
Breast cancers show a lack of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), despite 30% of tumors expressing EGFR. The mechanism of this resistance is unknown; however, we have recently shown that... more
Breast cancers show a lack of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), despite 30% of tumors expressing EGFR. The mechanism of this resistance is unknown; however, we have recently shown that Met kinase activity compensates for loss of EGFR kinase activity in cell culture models. Met has been implicated in the pathogenesis of breast tumors and therefore may cooperate with EGFR for tumor growth. Here we have found that EGFR phosphorylation and cell proliferation is in part regulated by Met expression. In addition, we found that Met constitutive phosphorylation occurred independent of the Met ligand hepatocyte growth factor (HGF). Ligand-independent Met phosphorylation is mediated by Met amplification, mutation, or overexpression and by Met interaction with other cell surface molecules. In SUM229 breast cancer cells, we found that Met was not amplified or mutated, however it was overexpressed. Met overexpression did not directly correlate ...
... Stephen P. Ethier, Katie L. Streicher, Michael E. Ray and Zeng Quan Yang Karmanos Cancer Institute, Detroit, MI and University of Michigan, Ann Arbor, MI. ... Clones expressing a single gene exhibited an IGF-independent phenotype, but... more
... Stephen P. Ethier, Katie L. Streicher, Michael E. Ray and Zeng Quan Yang Karmanos Cancer Institute, Detroit, MI and University of Michigan, Ann Arbor, MI. ... Clones expressing a single gene exhibited an IGF-independent phenotype, but were unable to grow in EGF-free medium. ...
More than 20 different PIK3CA gene mutations were identified in breast cancer with different frequencies. Whether these breast cancer associated mutations have similar biological effects is largely unknown. In this study, we established a... more
More than 20 different PIK3CA gene mutations were identified in breast cancer with different frequencies. Whether these breast cancer associated mutations have similar biological effects is largely unknown. In this study, we established a novel cell model using the lentivirus system to express 10 different PIK3CA genes (wild type and mutant) based on the human mammary epithelial cell MCF10A. We found that nine different PIK3CA mutants harbor different abilities to promote cell proliferation and EGF independent growth. In addition, most PIK3CA mutants (except for the wild type PIK3CA, the Q60K and the K111N mutants) had the ability to change the morphogenesis of the MCF10A cell in 3D Matrigel assay. Moreover, different PIK3CA mutants have different abilities to promote colony formation and cell invasion. We further observed that most of the PIK3CA mutants could activate p-AKT and p-p70-S6K in the absence of EGF stimulation. Finally, LY294002, a PI3K inhibitor, can effectively inhibit cell growth in cell lines with different PIK3CAs. Taken together, our results support the notion that different PIK3CA mutations differentially contribute to breast cancer transformation, and exploration of the therapeutic application of these mutations will benefit breast cancer patients with the PIK3CA mutations.
Research Interests: Breast Cancer, Biology, Enzyme Inhibitors, Cancer Research, Medicine, and 15 moreCell line, Humans, Breast Cancer Early Detecion and Treatment, Collagen, Lentivirus, Epidermal Growth Factor, Epithelial cells, Cell Proliferation, Chromones, Cell Growth, Laminin, Cell invasion, Breast Neoplasms, Drug combinations, and biological effect
Background Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid... more
Background Amplification of the 8p11-12 region has been found in approximately 15% of human breast cancer and is associated with poor prognosis. Previous genomic analysis has led us to identify the endoplasmic reticulum (ER) lipid raft-associated 2 (ERLIN2) gene as one of the candidate oncogenes within the 8p11-12 amplicon in human breast cancer, particularly in the luminal subtype. ERLIN2, an ER membrane protein, has recently been identified as a novel mediator of ER-associated degradation. Yet, the biological roles of ERLIN2 and molecular mechanisms by which ERLIN2 coordinates ER pathways in breast carcinogenesis remain unclear. Methods We established the MCF10A-ERLIN2 cell line, which stably over expresses ERLIN2 in human nontransformed mammary epithelial cells (MCF10A) using the pLenti6/V5-ERLIN2 construct. ERLIN2 over expressing cells and their respective parental cell lines were assayed for in vitro transforming phenotypes. Next, we knocked down the ERLIN2 as well as the ER st...
Research Interests: Pathology, Oncology, Medical Genetics, Breast Cancer, Biology, and 15 moreMembrane Proteins, Endoplasmic Reticulum Stress, Cancer Research, Medicine, Gene expression, RNA interference, Humans, Female, Endoplasmic Reticulum, Cluster Analysis, Carcinogenesis, Cell Survival, DNA binding proteins, Breast Neoplasms, and gene amplification
In a recent study, we identified frequent amplification of DNA copy number at chromosome 9p23-24 in cell lines derived from esophageal squamous cell carcinomas (ESCs), using comparative genomic hybridization. Because amplified regions... more
In a recent study, we identified frequent amplification of DNA copy number at chromosome 9p23-24 in cell lines derived from esophageal squamous cell carcinomas (ESCs), using comparative genomic hybridization. Because amplified regions often harbor oncogenes and/or other tumor-associated genes, and because 9p23-24 amplification had been reported in various other types of cancers, we used fluorescence in situ hybridization and Southern blot analysis to map the 9p23-24 amplicon. We then screened target genes/transcripts present within this amplicon by Northern blotting. With this strategy, we successfully cloned a novel gene, designated gene amplified in squamous cell carcinoma 1 (GASC1), that was amplified and overexpressed in several ESC cell lines. The deduced amino acid sequence of GASC1 contains two PHD-finger motifs and a PX domain. PHD-finger motifs are found in nuclear proteins that participate in chromatin-mediated transcriptional regulation and are present in a number of prot...
Research Interests:
Gene amplified in squamous cell carcinoma 1 (GASC1) is a member of Jumonji C-domain containing histone demethylases that play an essential role in affecting chromatin architecture and gene expression. The purpose of this study was to... more
Gene amplified in squamous cell carcinoma 1 (GASC1) is a member of Jumonji C-domain containing histone demethylases that play an essential role in affecting chromatin architecture and gene expression. The purpose of this study was to determine the expression features and the clinical significance of GASC1 in esophageal squamous cell carcinoma (ESCC). GASC1 expression was detected on tissue microarrays of ESCC samples in 185 cases using immunohistochemical staining. Strong nuclear staining for GASC1 was observed in a subset of ESCC samples. The nuclear expression of GASC1 was significantly associated with lymph node metastasis (P=0.030) and tumor-node metastasis stages (P=0.013). Kaplan-Meier survival analysis showed a tendency that high expression of GASC1 in the nucleus was associated with poor survival of ESCC patients, with a 5-year survival rate of 26.5%, as compared to 43.7% for patients with GASC1-negative/low expression. Furthermore, multivariate analysis revealed that high e...
Research Interests:
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD... more
A wide range of the epigenetic effectors that regulate chromatin modification, gene expression, genomic stability, and DNA repair contain structurally conserved domains called plant homeodomain (PHD) fingers. Alternations of several PHD finger-containing proteins (PHFs) due to genomic amplification, mutations, deletions, and translocations have been linked directly to various types of cancer. However, little is known about the genomic landscape and the clinical significance of PHFs in breast cancer. Hence, we performed a large-scale genomic and transcriptomic analysis of 98 PHF genes in breast cancer using TCGA and METABRIC datasets and correlated the recurrent alterations with clinicopathological features and survival of patients. Different subtypes of breast cancer had different patterns of copy number and expression for each PHF. We identified a subset of PHF genes that was recurrently altered with high prevalence, including PYGO2 (pygopus family PHD finger 2), ZMYND8 (zinc finge...
Research Interests:
KDM4 histone demethylases catalyze the removal of methyl marks from histone lysine residues to epigenetically regulate chromatin structure and gene expression. KDM4 expression is tightly regulated to insure proper function in diverse... more
KDM4 histone demethylases catalyze the removal of methyl marks from histone lysine residues to epigenetically regulate chromatin structure and gene expression. KDM4 expression is tightly regulated to insure proper function in diverse biological processes, such as cellular differentiation. Mounting evidence has shown that disrupting KDM4 expression is implicated in the establishment and progression of multiple diseases including cancer. In particular, genomic regions encoding the KDM4A, B and C genes are often amplified, disrupting normal cellular proliferation. Furthermore, KDM4 demethylases are promising druggable targets. In this review, we highlight the latest advances in characterizing the structures and regulatory mechanisms of KDM4 proteins, as well as our current understanding of their alterations and roles in tumorigenesis. We also review the reported KDM4 inhibitors and discuss their potential as therapeutic agents.
Research Interests:
Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated... more
Human methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In this study, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a large cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, METTL7B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at both the mRNA and protein levels in a spectrum of human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated the biological importance of METTL1, an m7G methyltransferase, in cancer cell growth and survival. Furthermore, functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the METTL1 cofactor WDR4, RNA regulators and DNA...
Research Interests:
Research Interests:
Three coronaviruses (CoVs): severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently identified SARS-CoV-2 in December 2019, have caused deadly pneumonia in... more
Three coronaviruses (CoVs): severe acute respiratory syndrome coronavirus (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), and the recently identified SARS-CoV-2 in December 2019, have caused deadly pneumonia in humans since the beginning of the 21st century. The SARS-CoV-2 causes coronavirus disease-19 (COVID-19) with influenza-like symptoms ranging from mild discomfort to severe lung injury and multi-organ failure, eventually leading to death. As of April 30, 2020, more than three million (3,175,207) COVID-19 cases were reported worldwide, and more than 220,000 (224,172) patients have died (https://www.who.int/emergencies/diseases/novel-coronavirus-2019). Effective treatments and vaccines for SARS-CoV-2 infection do not currently exist. Thus, it will be of great benefit to identify and repurpose already well-characterized compounds and approved drugs for use in combating COVID-19. CoVs are positive-sense RNA viruses that replicate in the cytoplasm of infected...
Research Interests:
Research Interests: Genetics and RNA biology
Chromodomain helicase DNA binding proteins (CHD) are characterized by N-terminal tandem chromodomains and a central ATP-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in... more
Chromodomain helicase DNA binding proteins (CHD) are characterized by N-terminal tandem chromodomains and a central ATP-dependent helicase domain. CHDs govern the cellular machinery's access to DNA, thereby playing critical roles in various cellular processes including transcription, proliferation, and DNA damage repair. Accumulating evidence demonstrates that mutation and dysregulation of CHDs are implicated in the pathogenesis of developmental disorders and cancer. However, we know little about genomic and transcriptomic alterations and the clinical significance of most CHDs in human cancer. We used TCGA and METABRIC datasets to perform integrated genomic and transcriptomic analyses of nine CHD genes in more than 10,000 primary cancer specimens from 32 tumor types, focusing on breast cancers. We identified associations among recurrent copy number alteration, gene expression, clinicopathological features, and patient survival. We found that CHD7 was the most commonly gained/amp...
Research Interests:
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, plays a key role in regulating mitochondrial energy production and cell survival. COX subunit VIIa polypeptide 2-like protein (COX7AR) is a novel COX... more
Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, plays a key role in regulating mitochondrial energy production and cell survival. COX subunit VIIa polypeptide 2-like protein (COX7AR) is a novel COX subunit that was recently found to be involved in mitochondrial supercomplex assembly and mitochondrial respiration activity. Here, we report that COX7AR is expressed in high energy-demanding tissues, such as brain, heart, liver, and aggressive forms of human breast cancer cells. Under cellular stress that stimulates energy metabolism, COX7AR is induced and incorporated into the mitochondrial COX complex. Functionally, COX7AR promotes cellular energy production in human mammary epithelial cells. Gain- and loss-of-function analysis demonstrates that COX7AR is required for human breast cancer cells to maintain higher rates of proliferation, clone formation, and invasion. In summary, our study revealed that COX7AR is a stress-inducible mitochondrial CO...
Research Interests:
Research Interests:
The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is... more
The histone lysine demethylase KDM4 subfamily, comprised of four members (A, B, C, and D), play critical roles in controlling transcription, chromatin architecture and cellular differentiation. We previously demonstrated that KDM4C is significantly amplified and overexpressed in aggressive basal-like breast cancers and functions as a transforming oncogene. However, information regarding the genomic and transcriptomic alterations of the KDM4 subfamily in different subtypes of breast cancer remains largely incomplete. Here, we conducted a meta-analysis of KDM4A, B, C and D in breast cancer and identified associations among recurrent copy number alterations, gene expression and breast cancer subtypes. We demonstrated that KDM4A and D are also significantly overexpressed in basal-like breast cancer, whereas KDM4B overexpression is more dominant in estrogen-receptor-positive, luminal breast cancer. Next, we investigated the therapeutic potential of a novel histone demethylase inhibitor, ...
Research Interests:
Research Interests:
Research Interests:
Cultured peripheral blood lymphocytes from ten normal individuals, treated with 0.075 M KCl at 37°C for 20 min, showed 0–2% cells in premature chromatid separation (PCS), a configuration with split centromeres and chromatids of most or... more
Cultured peripheral blood lymphocytes from ten normal individuals, treated with 0.075 M KCl at 37°C for 20 min, showed 0–2% cells in premature chromatid separation (PCS), a configuration with split centromeres and chromatids of most or all chromosomes. When treated for 30 min, they increased to 19% in the average, and at 45 min to 63%. Similar and significant effects of temperature and duration of hypotonic treatment on the frequencies of PCSs were found also in mitotic lymphocytes from patients with homozygous PCS trait, a cancer-prone disorder with >50% lymphocytes in PCS, mosaic variegated aneuploidy, and a variety of clinical manifestations; and from their heterozygous carrier parents. B lymphoblastoid cells from two infants with the homozygous PCS trait did not show PCSs when processed without hypotonic treatment. The frequencies of their PCSs increased with increasing temperature and duration of hypotonic treatment, attaining more than 65% after 20 min treatment and 90% after 45 min at 37°C. PCS is thus likely to be induced largely by hypotonic treatment. Treatment at 37°C for 20 min was found to be most suitable for the count of PCSs, in which the frequency of PCSs becomes almost zero in cells from normal individuals, and the difference in frequency of PCSs was most remarkable between the patients and heterozygous carriers, and between the heterozygous carriers and normal individuals. Chromosomes from the patients with the homozygous PCS trait tended to be long, and their PCSs tended to have a large number of widely separated sister chromatids. Chromosomes from normal individuals tended to be short, and the sister chromatids in their PCSs were set close to each other. © 2004 Wiley-Liss, Inc.
Research Interests:
Research Interests: Genetics, Polymorphism, Cancer, Breast Cancer, Apoptosis, and 16 moreHumans, Female, Risk factors, Galectin, Pilot study, Asian Americans, Genotype, Racial Disparities, European Continental Ancestry Group, Risk Factors, Amino Acid Sequence, Amino Acid Substitution Rates, Pilot Projects, Case Control Studies, Matrix Metalloproteinase, and Molecular Sequence Data
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon.... more
Previously, our group identified a novel amplicon at chromosome 9p24 in human esophageal and breast cancers, and cloned the novel gene, GASC1 (gene amplified in squamous cell carcinoma 1, also known as JMJD2C/KDM4C), from this amplicon. GASC1 is a histone demethylase involved in the deregulation of histone methylation in cancer cells. In the current study, we aimed to comprehensively characterize the genes in the 9p24 amplicon in human breast cancer. We performed extensive genomic analyses on a panel of cancer cell lines and narrowed the shortest region of overlap to approximately 2 Mb. Based on statistical analysis of copy number increase and overexpression, the 9p24 amplicon contains six candidate oncogenes. Among these, four genes (GASC1 UHRF2, KIAA1432 and C9orf123) are overexpressed only in the context of gene amplification while two genes (ERMP1 and IL33) are overexpressed independent of the copy number increase. We then focused our studies on the UHRF2 gene, which has a potential involvement in both DNA methylation and histone modification. Knocking down UHRF2 expression inhibited the growth of breast cancer cells specifically with 9p24 amplification. Conversely, ectopic overexpression of UHRF2 in non-tumorigenic MCF10A cells promoted cell proliferation. Furthermore, we demonstrated that UHRF2 has the ability to suppress the expression of key cell-cycle inhibitors, such as p16(INK4a), p21(Waf1/Cip1) and p27(Kip1). Taken together, our studies support the notion that the 9p24 amplicon contains multiple oncogenes that may integrate genetic and epigenetic codes and have important roles in human tumorigenesis.
Research Interests: Genetics, Functional Analysis, Statistical Analysis, Cancer, Breast Cancer, and 16 moreCell Cycle, Membrane Proteins, Apoptosis, Cell line, Humans, Epidermal Growth Factor/ErbB receptors, Female, Histone Modification, Oncogene, Squamous Cell Carcinoma, DNA methylation, Histone Methylation, Clinical Sciences, Oral Squamous Cell Carcinoma (OSCC), Cell Proliferation, and Breast Cancer Cells
Recently, we analysed the 8p11-12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found that SFRP1 (Secreted frizzled related protein 1) is frequently under... more
Recently, we analysed the 8p11-12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found that SFRP1 (Secreted frizzled related protein 1) is frequently under expressed even in breast tumours with copy number increases in this genomic region. SFRP1 encodes a WNT signalling antagonist, and plays a role in the development of multiple solid tumour types. In this study, we analysed methylation-associated silencing of the SFRP1 gene in breast cancer cells with the 8p11-12 amplicon, and investigated the tumour suppressor properties of SFRP1 in breast cancer cells. SFRP1 expression was markedly reduced in both the breast cancer cell lines and primary tumour specimens relative to normal primary human mammary epithelial cells even when SFRP1 is amplified. Suppression of SFRP1 expression in breast cancer cells with an SFRP1 gene amplification is associated with SFRP1 promoter methylation. Furthermore, restoration of SFRP1 expression suppressed the growth of breast cancer cells in monolayer, and inhibited anchorage independent growth. We also examined the relationship between the silencing of SFRP1 gene and WNT signalling in breast cancer. Ectopic SFRP1 expression in breast cancer cells suppressed both canonical and non-canonical WNT signalling pathways, and SFRP1 expression was negatively associated with the expression of a subset of WNT responsive genes including RET and MSX2. Thus, down-regulation of SFRP1 can be triggered by epigenetic and/or genetic events and may contribute to the tumourigenesis of human breast cancer through both canonical and non-canonical WNT signalling pathways. © 2009 UICC
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Breast cancer development is associated with gene amplification and over expression that is believed to have a causative role in oncogenesis. Previous studies have demonstrated that over expression of TC-1(C8orf4) mRNA occurs in ∼50% of... more
Breast cancer development is associated with gene amplification and over expression that is believed to have a causative role in oncogenesis. Previous studies have demonstrated that over expression of TC-1(C8orf4) mRNA occurs in ∼50% of breast cancer cell lines and primary tumor specimens. Here, we show that TC-1 has transforming properties in human mammary epithelial (HME) cells and its expression is mechanistically linked to FGFR signaling cascades. In vitro experiments demonstrate that TC-1 over expression mediates both anchorage-independent and growth factor-independent proliferation of HME cells. TC-1 was down regulated by the FGFR inhibitor PD173074 in the breast cancer cell line SUM-52 that also has an FGFR2 gene amplification and over expression. Furthermore, forced expression of FGFR2 in HME cells increased the level of expression of endogenous TC-1 mRNA. TC-1 has been implicated as a modulator of Wnt/β-catenin signaling in 293 cells and in gastric cancer cells. However, while we did find increased expression of a subset of β-catenin target genes in TC-1 over expressing cells, we did not find an association of TC-1 with global expression of β-catenin target genes in our cells. Taken together, our data suggest that TC-1 over expression is transforming and may link with the FGFR pathway in a subset of breast cancer. © 2007 Wiley-Liss, Inc.
Research Interests: Cancer, Breast Cancer, Gene expression, Signal Transduction, Humans, and 4 moreMice, Female, Animals, and Beta-Catenin
Research Interests:
Comparative genomic hybridization (CGH) was used to screen for genomic imbalances in cell lines derived from 13 nonpapillary renal-cell carcinomas (RCCs), two papillary RCCs, one renal squamous-cell carcinoma, and one transitional-cell... more
Comparative genomic hybridization (CGH) was used to screen for genomic imbalances in cell lines derived from 13 nonpapillary renal-cell carcinomas (RCCs), two papillary RCCs, one renal squamous-cell carcinoma, and one transitional-cell carcinoma of the renal pelvis. Aberrations were found in all 17 lines. The most frequent changes in nonpapillary RCC cell lines were gains of 5q (85%), 7q (69%), 8q (69%) and 1q (54%) and losses of 3p (92%), 8p (77%), 4q (62%) and 14q (54%). High-level gains (HLGs) were detected at 4q12, 5p, 5q23-33, 7q22-qter, 8q23-24, 10q21-qter, 12p and 12q13-22. By means of fluorescence in situ hybridization (FISH) we narrowed the smallest common region involving 5q gains to the genomic segment between D5S642 and D5S673, and found that the HLG at 4q12 possibly involved amplifications of c-kit and PDGFRA. Two papillary RCC cell lines showed gains of entire chromosomes 7, 12 and 17. The CGH data reported here should help to facilitate the choice of individual renal-tumor cell lines for exploring target genes in regions of interest.
Research Interests:
Five infants (two girls and three boys) from four families all had severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa... more
Five infants (two girls and three boys) from four families all had severe pre- and postnatal growth retardation, profound developmental delay, microcephaly, hypoplasia of the brain with Dandy-Walker complex or other posterior fossa malformations, and developed uncontrollable clonic seizures. Four infants developed Wilms tumors, and one showed cystic lesions in bilateral kidneys. All five infants showed variegated mosaic aneuploidy in cultured lymphocytes. In two infants whose chromosomes were prepared by us, 48.5%–83.2% lymphocytes showed total premature chromatid separation (PCS). Their parents had 3.5%–41.7% of their lymphocytes in total PCS. The remaining three infants and their parents, whose chromosomes were prepared at outside laboratories, tended to show lower frequencies of total PCS. Another five infants reported with the disorder were reviewed together with the five infants we described. Together, their clinical and cytogenetic manifestations were similar enough to suggest a syndrome. Seven of the 10 infants developed proven or probable Wilms tumors. The age at diagnosis of the tumors was younger than usual at 2–16 months. The tumors were bilateral in four infants and unilateral in three infants, and cystic changes were present in six infants. Two infants developed botryoid rhabdomyosarcoma. The carriers of the syndrome are thus liable to tumorigenesis. The possible role of mitotic checkpoint defects, proven in two infants with the syndrome (Matsuura et al. [2000: Am J Hum Genet 69:483–486]), was discussed in connection with tumor development and progression. © 2001 Wiley-Liss, Inc.
Research Interests:
The non-random amplification of DNA at 9p23-24 observed in various types of human cancers, including esophageal squamous cell carcinomas (ESCs), may reflect the locations of important tumor-associated genes. Our previous studies using ESC... more
The non-random amplification of DNA at 9p23-24 observed in various types of human cancers, including esophageal squamous cell carcinomas (ESCs), may reflect the locations of important tumor-associated genes. Our previous studies using ESC cell lines defined an amplicon in this region and identified a novel gene, GASC1, as a target of the amplification. Since different regions within the same chromosome arm are often involved in amplification in a syntenic or non-syntenic manner, we characterized the amplicon at 9p23-24 in 35 ESC cell lines (29 KYSE series and 6 YES series), and examined possible involvement of non-syntenic amplifications at 9p23-24 in 32 primary ESCs. Our results clearly indicated that two target regions for DNA amplification exist at 9p23-24; the major amplicon contains GASC1, and the minor one harbors a transcription factor, NFIB, centromeric to the GASC1 locus.
Research Interests:
Using comparative genomic hybridization (CGH), we investigated copy number aberrations in 29 esophageal squamous cell carcinoma (ESC) cell lines. All lines displayed numerous chromosome imbalances. The most frequent losses were observed... more
Using comparative genomic hybridization (CGH), we investigated copy number aberrations in 29 esophageal squamous cell carcinoma (ESC) cell lines. All lines displayed numerous chromosome imbalances. The most frequent losses were observed on chromosome 18q (65.5%), Xp (48.3%), 3p (44.8%), 4q (44.8%), 8p (41.4%), 11q23–25 (34.5%) and 4p (27.6%), whereas the most common copy number gains were noted at 8q (86.2%), 3q (82.8%), 5p (69%), 7p (69%), 20q (65.5%), 9q (55.2%), 11q (55.2%), 1q (48.3%), Xq (44.8%) and 18p (37.9%). High-level gains (HLGs) were detected at 3q26 (9 cases), 8q23 (6 cases), 5p14–15 (6 cases), 18p11.2–11.3 (6 cases), 3q27–28 (5 cases), 5p13 (3 cases), 7p14–15 (3 cases), 20q12–13 (3 cases), 11q13 (3 cases), 14q21 (2 cases), 20p11.2 (2 cases), 13q32 (2 case), and 1q32 (1 case). Among them, HLGs of 1q32 have been reported in other types of cancer, including glioblastoma and breast cancers. We successfully narrowed down the smallest common amplicon involving 1q-gain to the genomic segment between D1S414 and D1S2860 by fluorescence in situ hybridization (FISH). Southern and northern blot analysis clearly demonstrated that ATF3, human activating transcription factor-3 and CENPF, centromere protein F, mapped within this region, were significantly amplified and over-expressed in 1q32 amplicon.