Single‐nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish‐Ashkenazi descent |
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Authors: | Ronit I. Yarden Eitan Friedman Sally Metsuyanim Tzvia Olender Edna Ben‐Asher Moshe Z. Papa |
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Affiliation: | 1. Laboratory of Genomic Applications, Department of Surgical Oncology, Sheba Medical Center, Tel‐Hashomer, Israel;2. Department of Human Science, Georgetown University Medical Center, Washington DC;3. The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel‐Hashomer, Israel;4. The Crown Human Genome Center, Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel |
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Abstract: | Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2‐associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish‐Ashkenazi women for functional single‐nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53‐mediated apoptosis, as well as two tag‐SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing λ2 and Kaplan–Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44–54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049–7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205–11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289–1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles. © 2010 Wiley‐Liss, Inc. |
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Keywords: | BRCA1 BRCA2 breast and ovarian cancer risk modifier genes p53 CHEK2 Chk2 AKT1 PERP ZBKR1/ZNF350 Jewish‐Ashkenazi population |
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