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Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa
  1. Alessandro Pietro Aldera1,2,3,
  2. Jana van der Westhuizen3,
  3. Wan-Jung Tsai1,4,
  4. May J Krause3,
  5. Safiye Yildiz3,
  6. Komala Pillay1,4,
  7. Adam Boutall5,
  8. Raj Ramesar3
  1. 1Division of Anatomical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
  2. 2JDW Pathology Incorporated, Cape Town, South Africa
  3. 3Division 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
  4. 4National Health Laboratory Service, Cape Town, South Africa
  5. 5Division of General Surgery, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
  1. Correspondence to Dr Alessandro Pietro Aldera, Division of Anatomical Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7935, South Africa; alessandro.aldera{at}


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.

  • Colorectal Neoplasms

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Handling editor Yoh Zen.

  • Contributors Conceptualisation—RR and APA. Supervision—RR, KP and AB. Drafting the manuscript—APA. Reviewing the manuscript—all authors. Laboratory work—APA, JvdW, W-JT, MJK and SY. Data analysis—APA. Guarantor - APA.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.