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Mutations in BRCA-related breast and ovarian cancer in the South African Indian population: A descriptive study

  • Herkulaas MVE Combrink
    Correspondence
    Corresponding author.
    Affiliations
    Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

    Division of Human Genetics, National Health Laboratory Services, Universitas Hospital, Bloemfontein, South Africa
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  • Jaco Oosthuizen
    Affiliations
    Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

    Division of Human Genetics, National Health Laboratory Services, Universitas Hospital, Bloemfontein, South Africa
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  • Botma Visser
    Affiliations
    Department of Plant Sciences, Faculty of Natural and Agricultural Sciences, University of the Free State, Bloemfontein, South Africa
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  • Namitha Chabilal
    Affiliations
    Genetics Unit, Inkosi Albert Luthuli General Hospital, Durban, South Africa
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  • Ines Buccimazza
    Affiliations
    Department of Surgery, Faculty of Medicine, Inkosi Albert Luthuli General Hospital, Durban, South Africa
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  • William D Foulkes
    Affiliations
    Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, Montréal, QC, Canada

    Research Institute of the McGill University Health Centre, Montréal, QC, Canada

    Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montréal, QC, Canada
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  • Nerina C van der Merwe
    Affiliations
    Division of Human Genetics, Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa

    Division of Human Genetics, National Health Laboratory Services, Universitas Hospital, Bloemfontein, South Africa
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      Highlights

      • The South African Indian population represents a different genetic admixture compared to that of mainland India.
      • Twenty-eight different pathogenic heterozygotes were detected in 32 of the 223 patients in this study.
      • Comprehensive familial breast cancer testing is recommended for SA Indian patients as the pathogenic variants seem to be family- rather than population-specific.
      • Predictive testing of family members may relieve the financial burden on the country's healthcare system, as increased surveillance and appropriate management could prevent disease.

      Abstract

      Knowledge of the genetic landscape of a specific population group is vital for population-specific diagnosis and treatment of familial breast cancer. Although BRCA-related diagnostic testing has long been implemented in South Africa, the genotyping approach previously failed for the SA Indian population as it was based on other SA population groups. Because this population is uniquely admixed, the lack of population-specific data resulted in the implementation of comprehensive mutation screens for BRCA1/2. A total of 223 female patients were screened for clinically actionable variants. High-resolution melting analysis (HRMA) was used to screen 88 patients for DNA alterations in the coding and splice site boundaries of BRCA1 exons 2–9, BRCA1 exons 11–23, BRCA2 exons 2–9 and BRCA2 exons 12–27. The protein truncation test (PTT) was used to screen the three larger exons (BRCA1 exon 10 and BRCA2 exons 10 and 11) for protein termination changes. Multiplex ligation-dependent probe amplification (MLPA) was used to determine the presence of larger indels and possible copy number differences. Next Generation Sequencing (NGS) was performed on the remaining 135 samples. All potential variants were confirmed by performing Sanger DNA sequencing. The search revealed 28 different pathogenic heterozygotic variants, together with nine variants of unknown significance (VUS). The results suggested that the SA Indian population represents a different genetic admixture compared to that of mainland India, as only five pathogenic variants corresponded to those reported for mainland India. Familial breast cancer testing for SA Indian patients should therefore be performed as comprehensively as possible as the pathogenic variants seem to be family- rather than population-specific. Furthermore, predictive testing of family members will contribute to relieve the financial burden on the country's healthcare system, as increased surveillance and appropriate management could prevent disease.

      Keywords

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