title: Novel germline mutations and unclassified variants of BRCA1 and BRCA2 genes in Chinese women with familial breast/ovarian cancer.
abstract: 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.
authors: Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, 310022, China.
authors: Wen-Ming
authors: WM
authors: Cao
authors: Institute of Cancer Research, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors: Yun
authors: Y
authors: Gao
authors: Department of Breast Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors: Hong-Jian
authors: HJ
authors: Yang
authors: Department of Breast Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors: Shang-Nao
authors: SN
authors: Xie
authors: Department of Breast Cancer Surgery, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors: Xiao-Wen
authors: XW
authors: Ding
authors: Department of Clinical Laboratory, Zhejiang Cancer Hospital, Hangzhou, 310022, China.
authors: Zhi-Wen
authors: ZW
authors: Pan
authors: Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, 310022, China.
authors: Wei-Wu
authors: WW
authors: Ye
authors: Department of Medical Oncology, Zhejiang Cancer Hospital, 38 Guangji Road, Hangzhou, 310022, China. wxiaojia@yahoo.com.
authors: Xiao-Jia
authors: XJ
authors: Wang
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002681:China; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; C551750:BRCA2 protein, human