Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.
نویسندگان
چکیده
Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.
منابع مشابه
Functional Investigation of the Novel BRCA1variant (Glu1661Gly) byComputationalTools andYeastTranscription Activation Assay
Introduction: Mutations in the BRCA1 gene are major risk factors for breast and ovarian cancers. However, the relationship between some BRCA1 mutations and cancer risk remains largely unknown. Cancer risk predictions could be improved by evaluation of the impairment degree in the BRCA1 functions due to a specific mutation. This study aimed to assess the functional effect of a novel variant (Glu...
متن کاملFunctional Investigation of the Novel BRCA1variant (Glu1661Gly) byComputationalTools andYeastTranscription Activation Assay
Introduction: Mutations in the BRCA1 gene are major risk factors for breast and ovarian cancers. However, the relationship between some BRCA1 mutations and cancer risk remains largely unknown. Cancer risk predictions could be improved by evaluation of the impairment degree in the BRCA1 functions due to a specific mutation. This study aimed to assess the functional effect of a novel variant (Glu...
متن کاملFunctional investigation of the BRCA1 Val1714Gly and Asp1733Gly variants by computational tools and yeast transcription activation assay
Mutations in the BRCA1 gene are known to be a major cause of hereditary breast cancer. However, characterizing the point mutationsassociated with cancer in BRCA1 is challenging because the functional impact of most of them is still unknown. Nowadays, a variety of methods are employed to identify cancer-associated mutations in BRCA1. This study is aimed to ass...
متن کاملشناسایی جهش های جدید در اگزون 11 ژنBRCA1 در بیماران مبتلا به سرطان پستان ارثی
Introduction: Breast cancer is the most common malignancy in women worldwide. BRCA1 is a tumor suppressor gene that is involved in DNA-damage repair. One of the significant risk factors of breast cancer is the family history. BRCA1 gene consists of 24 exons that encode a protein with 1863 amino acids. Exon 11 is the largest exons and most of the disease-linked mutations have been found in it. I...
متن کاملمیزان بیان پروتئینBRCA1 در کارسینوم های مهاجم و درجای پستان و ارتباط آن با مارکر سلول های بنیادی سرطان پستان (CD44) و عوامل پیش آگهی تومور
Introduction : Breast cancer is the most common cancer and the second cause of cancer death among women. Despite recent developments in therapeutic tools about 25% of all the involved cases die annually. The clinical, molecular, and pathologic features of breast cancer in BRCA1 mutation carriers suggest that BRCA1 may function as a stem-cell regulator. The purpose of the current study was to ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Human molecular genetics
دوره 20 23 شماره
صفحات -
تاریخ انتشار 2011