The importance of analysis of long-range rearrangement of BRCA1 and BRCA2 in genetic diagnosis of familial breast cancer.
Germline BRCA gene mutations are reportedly associated with hereditary breast and ovarian cancers. Identification of BRCA mutations greatly improves the preventive strategies and management of breast cancer. Sanger sequencing has been the gold standard in identifying these mutations. However, 4-28% of inherited BRCA mutations may be due to large genomic rearrangements (LGRs), which could be missed by using Sanger sequencing alone. Our aim is to evaluate the pick-up rate of LGRs in our cohort. A total of 1,236 clinically high-risk patients with breast and/or ovarian cancers were recruited through The Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2014. Full gene sequencing (either Sanger or next generation sequencing) and multiplex ligation-dependent probe amplification (MLPA) were performed. We identified 120 deleterious BRCA mutations: 57 (4.61%) were in BRCA1 and 63 (5.10%) were in BRCA2. LGRs accounted for 6.67% (8 of 120) of all BRCA mutations, whereas 8.77 % (5 of 57) were BRCA1 mutations and 4.76% (3 of 63) were BRCA2 mutations. Through this integrated approach, both small nucleotide variations and LGRs could be detected. We suggest that MLPA should be incorporated into the standard practice for genetic testing to avoid false-negative results, which would greatly affect the management of these high-risk families.
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China; Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China; Department of Oncology, Stanford University School of Medicine, Stanford, California, USA; Department of Surgery, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China. Electronic address: akwong@asiabreastregistry.com.
Ava
A
Kwong
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Jiawei
J
Chen
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China.
Vivian Y
VY
Shin
Department of Surgery, The University of Hong Kong, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
John C W
JC
Ho
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
Fian B F
FB
Law
Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
Chun Hang
CH
Au
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
Tsun-Leung
TL
Chan
Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China; Department of Molecular Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China.
Edmond S K
ES
Ma
Department of Oncology, Stanford University School of Medicine, Stanford, California, USA.
James M
JM
Ford
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D010051:Ovarian Neoplasms / Q000235:genetics; D055815:Young Adult
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
BRCA; Large genmic rearrangements; hereditary breast and ovarian cancers; multiplex ligation-dependent probe amplification