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J Mol Diagn. 2016 Jul;18(4):580-94. doi: 10.1016/j.jmoldx.2016.03.005. Epub 2016 May 5.

Detection of Germline Mutation in Hereditary Breast and/or Ovarian Cancers by Next-Generation Sequencing on a Four-Gene Panel.

Author information

1
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.
2
Department of Surgery, The University of Hong Kong, Hong Kong, People's Republic of China.
3
Department of Molecular Pathology, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
4
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.
5
Department of Medical Physics and Research, Hong Kong Sanatorium & Hospital, Hong Kong, People's Republic of China.
6
Department of Medicine (Oncology), Stanford University School of Medicine, Stanford, California.

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.

PMID:
27157322
DOI:
10.1016/j.jmoldx.2016.03.005
[Indexed for MEDLINE]

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