{
  "abstract": "Aims Colorectal carcinoma (CRC) is a common cause of morbidity and mortality worldwide, and an emerging public health problem in sub-Saharan Africa. Several authors have described an increased frequency of mismatch repair-deficient (dMMR) CRC in sub-Saharan Africa, but these tumours remain poorly characterised molecularly. We sought to interrogate the somatic molecular genetic landscape of dMMR CRC in a cohort of young patients to better inform Lynch syndrome (LS) screening strategies and personalised medicine approaches in our setting.Methods 32 patients (aged <60 years) were identified with dMMR CRC. DNA was extracted from selected formalin-fixed paraffin-embedded (FFPE) tissue resection samples and subjected to amplicon-based next-generation sequencing (NGS).Results Pathogenic or likely pathogenic variants were detected in the corresponding MMR gene in 14 of 18 (78%) MLH1/PMS2-deficient tumours, 5 of 8 (63%) MSH2/MSH6-deficient tumours, 1 of 4 (25%) tumours with isolated MSH6 loss and 0 of 2 tumours with isolated PMS2 loss. Previously unreported variants were identified in MLH1 (three) and MSH2 (one). Cases with a variant allele frequency suggesting a germline mutation were identified in MLH1 (eight), MSH2 (two) and MSH6 (one). Only one MMR gene variant was detected in more than one patient (MLH1 p.Q510*). Four POLE/POLD1 exonuclease domain variants were identified, one of which was previously unreported.Conclusion The spectrum of disease-causing MMR gene variants in our population necessitates NGS testing for LS screening. This study also highlights the role of somatic testing on readily available FFPE samples to generate data on the epidemiology of CRC in different settings.",
  "authors": [
    {
      "affiliations": [
        "Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa",
        "JDW Pathology Incorporated, Cape Town, South Africa",
        "Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"
      ],
      "name": "Alessandro Pietro Aldera"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"
      ],
      "name": "Jana van der Westhuizen"
    },
    {
      "affiliations": [
        "Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa",
        "National Health Laboratory Service, Cape Town, South Africa"
      ],
      "name": "Wan-Jung Tsai"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"
      ],
      "name": "May J Krause"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"
      ],
      "name": "Safiye Yildiz"
    },
    {
      "affiliations": [
        "Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa",
        "National Health Laboratory Service, Cape Town, South Africa"
      ],
      "name": "Komala Pillay"
    },
    {
      "affiliations": [
        "Division of General Surgery, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa"
      ],
      "name": "Adam Boutall"
    },
    {
      "affiliations": [
        "Division of Human Genetics, Department of Pathology, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa"
      ],
      "name": "Raj Ramesar"
    }
  ],
  "title": "Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa",
  "uid": "ded70e19-780d-53d5-a2d2-a18685752d99"
}