Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is... more Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)-2, -3, and -9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE. Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP-2, -3, and -9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP-3 plasma levels with the risk of IADE, determination of the MMP-3 5A/6A polymorphism was carried out. IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP-2, -3, and -9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP-3 tertile (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.17-5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03-2.55). In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP-3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP-3. These results suggest that MMP-3 may play a role in IADE.
Linkage analysis was performed in a previously described family segregating for an X-linked progr... more Linkage analysis was performed in a previously described family segregating for an X-linked progressive neurological disorder [Bertini et al., 1992]. In three generations, the disease was inherited from the mothers in seven affected males (Fig. 1). Five had severe congenital hypotonia and died during the first year of life. Two other boys (maternal cousins) were found to have severe congenital ataxia, late-onset progressive myoclonic encephalopathy, and selective macular degeneration; brain CT-scan showed moderate cerebellar vermis hypoplasia. Linkage analysis was carried out in 12 informative relatives using 35 microsatellite markers (Généthon) evenly distributed on the X chromosome. A multipoint analysis showed a significant linkage (Z > 2) between the disease and three markers in the Xp22.33 region: DYS403 (Z = 2.37, theta = 0) which maps in the pseudoautosomal region, DXS7099 (Z = 2.45, theta = 0), and DXS7100 (Z = 2.48, theta = 0). Further linkage analysis with more telomeric markers will refine the location of this severe X-linked encephalopathy.
Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to ... more Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. In this work, we tested the hypothesis that POLH variants could be associated with melanoma risk.A common non-synonymous POLH variant, c.1783A>G p.M595V, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma (n = 123), sporadic multiple melanomas (n = 65) and a melanoma associated with a skin carcinoma (n = 13).Overall, the c.1783G, p.595V allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P-value = 1.17 × 10–3, odds ratio (OR) = 1.86 [1.27–2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy (P-value = 7.7 × 10–4, OR = 1.84 [1.29–2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects.Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data.
Colorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has ... more Colorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has been poorly studied. This study examined the prevalence of deficient mismatch repair phenotype (dMMR) and BRAF mutations according to age. MMR phenotype was prospectively determined by molecular analysis in patients of all ages undergoing surgery for CRC. BRAF V600E mutation status was analysed in a subset of dMMR tumours. A total of 754 patients who underwent surgery between 2005 and 2008 were included in the study. Amongst them, 272 (36%) were ≥75years old. The proportion of women <75 was 38% and that ≥75 was 53% (p<0.0001). The prevalence of dMMR was 19.4% in patients ≥75 and 10.7% in patients <75 (p=0.0017). For patients ≥75, the prevalence of dMMR was significantly higher in women than in men (27% vs 10.2%, respectively; p=0.003) but was similar in women and men <75 (12.5% vs 9.7%, respectively; p=0.4). We examined BRAF mutation status in 80 patients with dMMR tumours. The V600E BRAF mutation was significantly more frequent in patients ≥75 than in patients <75 (72.2% vs 11.4%, respectively; p<0.001). In patients ≥75, there was no difference in the prevalence of the BRAF V600E mutation according to sex (78% in women and 70% in men, p=0.9). The prevalence of dMMR in CRC is high in patients over 75. In elderly patients, dMMR tumours are significantly more frequent in women than in men. The BRAF mutation is frequent in elderly patients with CRC.
The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of ... more The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of BCC (basocellular carcinoma) and Gorlin's syndrome has greatly improved our knowledge on the mechanism of development of these tumors. For the first time, murine models have been developed allowing to further understand other molecular events implicated in such tumors as well as providing in vivo models to search for new curative or preventive therapeutical strategies which would be helpful to control CBC multiple forms, that are often disabling.
In contrast with cutaneous squamous cell carcinomas, the risk for development of melanoma does no... more In contrast with cutaneous squamous cell carcinomas, the risk for development of melanoma does not appear to be greatly increased after solid organ transplantation, except for the rare case of donor-derived melanoma. The clinical aspects of melanoma in organ transplant recipients are discussed elsewhere, but it would seem that genetic susceptibility to melanoma is likely to be of similar relevance to the immunosuppressed individual as to the immunocompetent individual. Because the outcome of melanoma, particularly thicker melanomas, is worse after transplantation (Matin et al., in press), patients who come from melanoma-prone families or who have a history of multiple melanomas must be carefully counselled before transplantation. Extremely close skin surveillance and a low threshold for biopsy of melanocytic lesions would be advisable.
Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is... more Intracranial arterial dolichoectasia (IADE), also called dilatative arteriopathy of the brain, is defined as an increase in length and diameter of intracranial arteries. Abdominal aortic aneurysm and ectasia of coronary arteries have been reported in association with IADE. In both conditions, a dysfunction of matrix metalloproteinases (MMP)-2, -3, and -9 have been found. Our aim was to investigate these MMP pathways in stroke patients with IADE. Five hundred ten Caucasians patients with brain infarction were consecutively recruited at 12 centers. The diagnosis of IADE was made by consensus between 2 neurologists based on magnetic resonance imaging scans. Determination of MMP-2, -3, and -9 plasma levels was centralized in 1 laboratory. Because we found a threshold effect of MMP-3 plasma levels with the risk of IADE, determination of the MMP-3 5A/6A polymorphism was carried out. IADE was identified in 12% of stroke patients. There was no association of IADE with mean MMP-2, -3, and -9 plasma levels. After categorization of MMP plasma levels into tertiles, we found a higher risk of IADE with the lowest MMP-3 tertile (adjusted odds ratio [OR], 2.48; 95% confidence interval [CI], 1.17-5.23). In genotype analysis, there was a significant additive effect of the 5A allele on the risk of IADE, with an adjusted OR of 1.62 (95% CI, 1.03-2.55). In this cohort of stroke patients of Caucasian ancestry, IADE was associated with low MMP-3 plasma levels and with the 5A/6A polymorphism of the promoter region of MMP-3. These results suggest that MMP-3 may play a role in IADE.
Linkage analysis was performed in a previously described family segregating for an X-linked progr... more Linkage analysis was performed in a previously described family segregating for an X-linked progressive neurological disorder [Bertini et al., 1992]. In three generations, the disease was inherited from the mothers in seven affected males (Fig. 1). Five had severe congenital hypotonia and died during the first year of life. Two other boys (maternal cousins) were found to have severe congenital ataxia, late-onset progressive myoclonic encephalopathy, and selective macular degeneration; brain CT-scan showed moderate cerebellar vermis hypoplasia. Linkage analysis was carried out in 12 informative relatives using 35 microsatellite markers (Généthon) evenly distributed on the X chromosome. A multipoint analysis showed a significant linkage (Z > 2) between the disease and three markers in the Xp22.33 region: DYS403 (Z = 2.37, theta = 0) which maps in the pseudoautosomal region, DXS7099 (Z = 2.45, theta = 0), and DXS7100 (Z = 2.48, theta = 0). Further linkage analysis with more telomeric markers will refine the location of this severe X-linked encephalopathy.
Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to ... more Xeroderma pigmentosum variant (XPV) is a rare recessive autosomal genodermatosis predisposing to multiple early onset skin cancers, including melanoma. XPV results from mutations of the POLH gene that encodes a DNA translesion polymerase. In this work, we tested the hypothesis that POLH variants could be associated with melanoma risk.A common non-synonymous POLH variant, c.1783A>G p.M595V, was genotyped in 1075 melanoma patients and in 1091 ethnic-matched controls from France. In addition, we searched for rare POLH variants by sequencing the entire coding sequence in 201 patients having a familial history of melanoma (n = 123), sporadic multiple melanomas (n = 65) and a melanoma associated with a skin carcinoma (n = 13).Overall, the c.1783G, p.595V allele was statistically associated with melanoma (respective allelic frequencies, 0.040 versus 0.022, P-value = 1.17 × 10–3, odds ratio (OR) = 1.86 [1.27–2.71]), which was further confirmed by a meta-analysis including 274 patients and 174 matched controls from Italy (P-value = 7.7 × 10–4, OR = 1.84 [1.29–2.63]). Interestingly, three non-synonymous POLH variants were identified in three patients (c.295G>A p.V99M, c.815T>C p.I272T and c.1745C>T p.S582L) which were absent in 352 chromosome controls from healthy subjects.Besides severe deficiencies in translesion synthesis which are major risks factors for skin carcinomas and melanomas, less deleterious POLH variants could act as low penetrance melanoma predisposing alleles. The ongoing identification of genetic markers implied in skin cancer predisposition could help to identify high-risk subjects as targets for clinical follow-up. Replication studies in other populations are awaited to assess these data.
Colorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has ... more Colorectal cancer (CRC) occurs mostly in the elderly. However, the biology of CRC in elderly has been poorly studied. This study examined the prevalence of deficient mismatch repair phenotype (dMMR) and BRAF mutations according to age. MMR phenotype was prospectively determined by molecular analysis in patients of all ages undergoing surgery for CRC. BRAF V600E mutation status was analysed in a subset of dMMR tumours. A total of 754 patients who underwent surgery between 2005 and 2008 were included in the study. Amongst them, 272 (36%) were ≥75years old. The proportion of women <75 was 38% and that ≥75 was 53% (p<0.0001). The prevalence of dMMR was 19.4% in patients ≥75 and 10.7% in patients <75 (p=0.0017). For patients ≥75, the prevalence of dMMR was significantly higher in women than in men (27% vs 10.2%, respectively; p=0.003) but was similar in women and men <75 (12.5% vs 9.7%, respectively; p=0.4). We examined BRAF mutation status in 80 patients with dMMR tumours. The V600E BRAF mutation was significantly more frequent in patients ≥75 than in patients <75 (72.2% vs 11.4%, respectively; p<0.001). In patients ≥75, there was no difference in the prevalence of the BRAF V600E mutation according to sex (78% in women and 70% in men, p=0.9). The prevalence of dMMR in CRC is high in patients over 75. In elderly patients, dMMR tumours are significantly more frequent in women than in men. The BRAF mutation is frequent in elderly patients with CRC.
The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of ... more The recent discovery of the role of the Patched Sonic Hedgehog pathway in the physiopathogeny of BCC (basocellular carcinoma) and Gorlin's syndrome has greatly improved our knowledge on the mechanism of development of these tumors. For the first time, murine models have been developed allowing to further understand other molecular events implicated in such tumors as well as providing in vivo models to search for new curative or preventive therapeutical strategies which would be helpful to control CBC multiple forms, that are often disabling.
In contrast with cutaneous squamous cell carcinomas, the risk for development of melanoma does no... more In contrast with cutaneous squamous cell carcinomas, the risk for development of melanoma does not appear to be greatly increased after solid organ transplantation, except for the rare case of donor-derived melanoma. The clinical aspects of melanoma in organ transplant recipients are discussed elsewhere, but it would seem that genetic susceptibility to melanoma is likely to be of similar relevance to the immunosuppressed individual as to the immunocompetent individual. Because the outcome of melanoma, particularly thicker melanomas, is worse after transplantation (Matin et al., in press), patients who come from melanoma-prone families or who have a history of multiple melanomas must be carefully counselled before transplantation. Extremely close skin surveillance and a low threshold for biopsy of melanocytic lesions would be advisable.
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