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Breast Cancer Res Treat. 2017 Oct;165(3):687-697. doi: 10.1007/s10549-017-4356-8. Epub 2017 Jun 29.

Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia.

Author information

1
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, NCI/NIH, Bethesda, Rockville, MD, USA. royang@mail.nih.gov.
2
Department of Radiotherapy, Oncology and Palliative Care, Sarawak General Hospital, Kuching, Sarawak, Malaysia.
3
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, NCI/NIH, Bethesda, Rockville, MD, USA.
4
Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada.
5
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
6
Department of Biology, Trinity Washington University, Washington, DC, USA.

Abstract

PURPOSE:

To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population.

METHODS:

Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site.

RESULTS:

We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86% for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also identified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites.

CONCLUSION:

Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.

KEYWORDS:

BRCA1/2; Breast cancer; Germline mutation; Malaysia; PALB2

PMID:
28664506
DOI:
10.1007/s10549-017-4356-8
[Indexed for MEDLINE]

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