title: Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel.
abstract: Mutation in BRCA1/BRCA2 genes accounts for 20% of familial breast cancers, 5% to 10% of which may be due to other less penetrant genes which are still incompletely studied. Herein, a four-gene panel was used to examine the prevalence of BRCA1, BRCA2, TP53, and PTEN in hereditary breast and ovarian cancers in Southern Chinese population. In this cohort, 948 high-risk breast and/or ovarian patients were recruited for genetic screening by next-generation sequencing (NGS). The performance of our NGS pipeline was evaluated with 80 Sanger-validated known mutations and eight negative cases. With appropriate bioinformatics analysis pipeline, the detection sensitivity of NGS is comparable with Sanger sequencing. The prevalence of BRCA1/BRCA2 germline mutations was 9.4% in our Chinese cohort, of which 48.8% of the mutations arose from hotspot mutations. With the use of a tailor-made algorithm, HomopolymerQZ, more mutations were detected compared with single mutation detection algorithm. The frequencies of PTEN and TP53 were 0.21% and 0.53%, respectively, in the Southern Chinese patients with breast and/or ovarian cancers. High-throughput NGS approach allows the incorporation of control cohort that provides an ethnicity-specific data for polymorphic variants. Our data suggest that hotspot mutations screening such as SNaPshot could be an effective preliminary screening alternative adopted in a standard clinical laboratory without NGS setup.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, People's Republic of China; Department of Surgery, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China; Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, People's Republic of China. Electronic address: akwong@asiabreastregistry.com.
authors.forename: Ava
authors.initials: A
authors.lastname: Kwong
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, People's Republic of China.
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Shin
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Chun H
authors.initials: CH
authors.lastname: Au
authors.affiliation: Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, People's Republic of China; Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Fian B F
authors.initials: FB
authors.lastname: Law
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Dona N
authors.initials: DN
authors.lastname: Ho
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Bui K
authors.initials: BK
authors.lastname: Ip
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Anthony T C
authors.initials: AT
authors.lastname: Wong
authors.affiliation: Department of Medical Physics and Research, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Silvia S
authors.initials: SS
authors.lastname: Lau
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Rene M Y
authors.initials: RM
authors.lastname: To
authors.affiliation: Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Gigi
authors.initials: G
authors.lastname: Choy
authors.affiliation: Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, California.
authors.forename: James M
authors.initials: JM
authors.lastname: Ford
authors.affiliation: Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, People's Republic of China; Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Edmond S K
authors.initials: ES
authors.lastname: Ma
authors.affiliation: Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, People's Republic of China; Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
authors.forename: Tsun L
authors.initials: TL
authors.lastname: Chan
mesh_terms: D000328:Adult; D000465:Algorithms; D000483:Alleles; D005260:Female; D005787:Gene Frequency; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D061325:Hereditary Breast and Ovarian Cancer Syndrome / Q000175:diagnosis* / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics; D015203:Reproducibility of Results; D057188:Workflow
chemical_list: D051059:PTEN Phosphohydrolase