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Breast Cancer Research and Treatment

, Volume 165, Issue 3, pp 687–697 | Cite as

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

  • Xiaohong R. Yang
  • Beena C. R. Devi
  • Hyuna Sung
  • Jennifer Guida
  • Eliseos J. Mucaki
  • Yanzi Xiao
  • Ana Best
  • Lisa Garland
  • Yi Xie
  • Nan Hu
  • Maria Rodriguez-Herrera
  • Chaoyu Wang
  • Kristine Jones
  • Wen Luo
  • Belynda Hicks
  • Tieng Swee Tang
  • Karobi Moitra
  • Peter K. Rogan
  • Michael Dean
Epidemiology

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

Breast cancer Germline mutation BRCA1/2 PALB2 Malaysia 

Notes

Acknowledgements

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.

Supplementary material

10549_2017_4356_MOESM1_ESM.xlsx (24 kb)
Supplementary material 1 (XLSX 24 kb)

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Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2017

Authors and Affiliations

  • Xiaohong R. Yang
    • 1
  • Beena C. R. Devi
    • 2
  • Hyuna Sung
    • 1
  • Jennifer Guida
    • 1
  • Eliseos J. Mucaki
    • 3
  • Yanzi Xiao
    • 1
  • Ana Best
    • 1
  • Lisa Garland
    • 4
  • Yi Xie
    • 1
  • Nan Hu
    • 1
  • Maria Rodriguez-Herrera
    • 1
  • Chaoyu Wang
    • 1
  • Kristine Jones
    • 4
  • Wen Luo
    • 4
  • Belynda Hicks
    • 4
  • Tieng Swee Tang
    • 2
  • Karobi Moitra
    • 1
    • 5
  • Peter K. Rogan
    • 3
  • Michael Dean
    • 1
  1. 1.Division of Cancer Epidemiology and Genetics, National Cancer InstituteNational Institutes of Health, NCI/NIHRockvilleUSA
  2. 2.Department of Radiotherapy, Oncology and Palliative CareSarawak General HospitalKuchingMalaysia
  3. 3.Department of Biochemistry, Schulich School of Medicine and DentistryUniversity of Western OntarioLondonCanada
  4. 4.Cancer Genomics Research Laboratory, Leidos Biomedical ResearchFrederick National Laboratory for Cancer ResearchFrederickUSA
  5. 5.Department of BiologyTrinity Washington UniversityWashingtonUSA

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