Rare mutations in XRCC2 increase the risk of breast cancer.
نویسندگان
چکیده
An exome-sequencing study of families with multiple breast-cancer-affected individuals identified two families with XRCC2 mutations, one with a protein-truncating mutation and one with a probably deleterious missense mutation. We performed a population-based case-control mutation-screening study that identified six probably pathogenic coding variants in 1,308 cases with early-onset breast cancer and no variants in 1,120 controls (the severity grading was p < 0.02). We also performed additional mutation screening in 689 multiple-case families. We identified ten breast-cancer-affected families with protein-truncating or probably deleterious rare missense variants in XRCC2. Our identification of XRCC2 as a breast cancer susceptibility gene thus increases the proportion of breast cancers that are associated with homologous recombination-DNA-repair dysfunction and Fanconi anemia and could therefore benefit from specific targeted treatments such as PARP (poly ADP ribose polymerase) inhibitors. This study demonstrates the power of massively parallel sequencing for discovering susceptibility genes for common, complex diseases.
منابع مشابه
Polymorphisms in RAD51, XRCC2, and XRCC3 are not related to breast cancer risk.
Highly penetrant, but rare, mutations in genes involved in double-strand break repair (i.e., BRCA1 and BRCA2) are associated with a risk for breast cancer of 40% to 65% by age 70 years (1, 2). Polymorphisms in other double-strand break repair genes are thought to contribute to the risk for the disease, either independently or through modifying the risk associated with rare mutations. This study...
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BACKGROUND Although inherited breast cancer has been associated with germline mutations in genes that are functionally involved in the DNA homologous recombination repair (HRR) pathway, including BRCA1, BRCA2, TP53, ATM, BRIP1, CHEK2 and PALB2, about 70% of breast cancer heritability remains unexplained. Because of their critical functions in maintaining genome integrity and already well-establ...
متن کاملRAD51, XRCC3, and XRCC2 mutation screening in Finnish breast cancer families
Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51...
متن کاملDouble-strand break repair gene polymorphisms and risk of breast or ovarian cancer.
Deficiencies in DNA repair have been hypothesized to increase cancer risk and excess cancer incidence is a feature of inherited diseases caused by defects in DNA damage recognition and repair. We investigated, using a case-control design, whether the double-strand break repair gene polymorphisms RAD51 5' untranslated region -135 G > C, XRCC2 R188H G > A, and XRCC3 T241M C > T were associated wi...
متن کاملCorrelation between selected XRCC2, XRCC3 and RAD51 gene polymorphisms and primary breast cancer in women in Pakistan.
Genetic polymorphisms in homologous recombination repair genes cause an abnormal development of cancerous cells. In the present study we evaluated the possibility of breast cancer association with single nucleotide polymorphisms of RAD51, XRCC2 and XRCC3 genes. Polymorphisms selected in this study were RAD51 135G/C, XRCC2 Arg188His; and XRCC3 Thr241Met. Each polymorphism was genotyped using Pol...
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ورودعنوان ژورنال:
- American journal of human genetics
دوره 90 4 شماره
صفحات -
تاریخ انتشار 2012