Abstract
BackgroundGermline mutations in the BRCA1 and BRCA2 genes greatly increase a woman’s risk of developing breast and/or ovarian cancer. The prevalence and distribution of such mutations differ across races/ethnicities. Several studies have investigated Chinese women with high-risk breast cancer, but the full spectrum of the mutations in these two genes remains unclear.MethodsIn this study, 133 unrelated Chinese women with familial breast/ovarian cancer living in Zhejiang, eastern China, were enrolled between the years 2008 and 2014. The complete coding regions and exon-intron boundaries of BRCA1 and BRCA2 were screened by PCR-sequencing assay. Haplotype analysis was performed to confirm BRCA1 and BRCA2 founder mutations. In silico predictions were performed to identify the non-synonymous amino acid changes that were likely to disrupt the functions of BRCA1 and BRCA2.ResultsA total of 23 deleterious mutations were detected in the two genes in 31 familial breast/ovarian cancer patients with a total mutation frequency of 23.3 % (31/133). The highest frequency of 50.0 % (8/16) was found in breast cancer patients with a history of ovarian cancer. The frequencies of BRCA1 and BRCA2 mutations were 13.5 % (18/133) and 9.8 % (13/133), respectively. We identified five novel deleterious mutations (c.3295delC, c.3780_3781delAG, c.4063_4066delAATC, c.5161 > T and c.5173insA) in BRCA1 and seven (c.1-40delGA, c.4487delC, c.469_473delAAGTC, c.5495delC, c.6141T > A, c.6359C > G and c.7588C > T) in BRCA2, which accounted for 52.2 % (12/23) of the total mutations. Six recurrent mutations were found, including four (c.3780_3781delAG, c.5154G > A, c.5468-1del8 and c.5470_5477del8) in BRCA1 and two (c.3109C > T and c.5682C > G) in BRCA2. Two recurrent BRCA1 mutations (c.5154G > A and c.5468-1del8) were identified as putative founder mutations. We also found 11 unclassified variants, and nine of these are novel. The possibility was that each of the non-synonymous amino acid changes would disrupt the function of BRCA1 and BRCA2 varied according to the different algorithms used.ConclusionsBRCA1 and BRCA2 mutations accounted for a considerable proportion of hereditary breast/ovarian cancer patients from eastern China and the spectrum of the mutations of these two genes exhibited some unique features. The two BRCA1 putative founder mutations may provide a cost-effective option to screen Chinese population, while founder effects of the two mutations should be investigated in a lager sample size of patients.
Highlights
Germline mutations in the BRCA1 and BRCA2 genes greatly increase a woman’s risk of developing breast and/or ovarian cancer
We found that the spectrum of BRCA1 and BRCA2 germline mutations in Chinese high risk breast cancer patients are much smaller than those in Caucasian patients, and little has been recognized in this field
Patient features A total of 133 unrelated patients with personal and family histories of breast and/or ovarian cancer underwent BRCA1 and BRCA2 germline mutation screening
Summary
Germline mutations in the BRCA1 and BRCA2 genes greatly increase a woman’s risk of developing breast and/or ovarian cancer. The overall mutation frequencies in these two genes in Chinese high risk breast cancer patients ranged from 8.3 to 27.8 %, depending on the detection methods and patient inclusion criteria used. These frequencies are much lower than the 25–40 % in BRCA1 and 6–15 % in BRCA2 that have been observed in Caucasian populations [22]. Because germline mutations in BRCA1 and BRCA2 greatly increase a woman’s risk of developing breast and/or ovarian cancer, and the prevalence and distribution of the germline mutations differ in different races/ ethnicities, we were interested in identifying the full spectrum of these mutations in high-risk female breast cancer patients in the Chinese population
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