Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis

• Published in: PloS one 2012-09, Vol.7 (9), p.e43994-e43994
• Main Authors: Kwong, Ava, Ng, Enders Kai On, Wong, Chris Lei Po, Law, Fian Bic Fai, Au, Tommy, Wong, Hong Nei, Kurian, Allison W, West, Dee W, Ford, James M, Ma, Edmond Siu Kwan
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Asian Continental Ancestry Group - genetics; Biology; BRCA1 protein; BRCA1 Protein - genetics; BRCA2 protein; BRCA2 Protein - genetics; Breast cancer; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Cancer; Cancer genetics; Cancer research; Care and treatment; Case-Control Studies; China; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA sequencing; Epidemiology; Exons; Female; Founder Effect; Gene mutation; Gene sequencing; Genetic analysis; Genetic aspects; Genetic counseling; Genetic Predisposition to Disease; Genetic screening; Genetics; Haplotypes; Haplotypes - genetics; Health aspects; Health risk assessment; Health risks; High resolution; Humans; Male; Medicine; Melting; Middle Aged; Mutation; Mutation - genetics; Nucleic Acid Denaturation - genetics; Ovarian cancer; Ovarian carcinoma; Patients; Populations; Reproducibility of Results; Risk assessment; Risk groups; Screening; Sequence Analysis, DNA - methods; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0043994

Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China. A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM) analysis. Among the 451 probands analyzed, 69 (15.3%) deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT) accounted for 34.5% (10/29) of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA) accounted for 40% (16/40) of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated. In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.