Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in Chinese women with familial breast/ovarian cancer

被引:24
作者
Cao, Wen-Ming [1 ]
Gao, Yun [2 ]
Yang, Hong-Jian [3 ]
Xie, Shang-Nao [3 ]
Ding, Xiao-Wen [3 ]
Pan, Zhi-Wen [4 ]
Ye, Wei-Wu [1 ]
Wang, Xiao-Jia [1 ]
机构
[1] Zhejiang Canc Hosp, Dept Med Oncol, Hangzhou 310022, Zhejiang, Peoples R China
[2] Zhejiang Canc Hosp, Inst Canc Res, Hangzhou 310022, Zhejiang, Peoples R China
[3] Zhejiang Canc Hosp, Dept Breast Canc Surg, Hangzhou 310022, Zhejiang, Peoples R China
[4] Zhejiang Canc Hosp, Dept Clin Lab, Hangzhou 310022, Zhejiang, Peoples R China
来源
BMC CANCER | 2016年 / 16卷
关键词
BRCA1; BRCA2; Germline mutation; Unclassified variants; Founder mutation; Chinese women; HEREDITARY BREAST-CANCER; GENOMIC REARRANGEMENTS; AFFECTED RELATIVES; RISK; PREVALENCE; POPULATION;
D O I
10.1186/s12885-016-2107-6
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Germline 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. Methods: In 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. Results: A 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. Conclusions: BRCA1 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.
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页数:9
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