Prevalence and spectrum of germline rare variants in BRCA1/2 and PALB2 among breast cancer cases in Sarawak, Malaysia
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To characterize the spectrum of germline mutations in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population.
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.
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.
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.
KeywordsBreast cancer Germline mutation BRCA1/2 PALB2 Malaysia
This research was supported by the Intramural Research Program of the NIH, National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (DCEG), and Natural Sciences and Engineering Research Council of Canada-Discovery Grant [371758-2009], Canadian Foundation for Innovation, Canada Research Chairs and Cytognomix Inc.
Compliance with ethical standards
Conflicts of interest
PKR is the inventor of US Patent 5867402 and other patents pending, which underlie the prediction and validation of mutations. He cofounded Cytognomix Inc., which is developing software based on this technology for complete genome or exome mutation analysis.
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