Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer

Safiye Yildiz; Takudzwa N Musarurwa; Ursula Algar; Ramadhani Chambuso; George Rebello; Paul A Goldberg; Raj Ramesar

doi:10.3389/fonc.2023.1253867

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer

Front Oncol. 2023 Oct 27:13:1253867. doi: 10.3389/fonc.2023.1253867. eCollection 2023.

Authors

Safiye Yildiz¹, Takudzwa N Musarurwa¹, Ursula Algar², Ramadhani Chambuso¹, George Rebello¹, Paul A Goldberg², Raj Ramesar¹

Affiliations

¹ UCT/MRC Genomic and Precision Medicine Research Unit, Division of Human Genetics, Department of Pathology, Institute of Infectious Disease and Molecular Medicine, University of Cape Town and Affiliated Hospitals, Cape Town, South Africa.
² The Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South Africa.

Abstract

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel.

Materials and methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR.

Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes.

Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

Keywords: South African populations; early-onset colorectal cancer; genetic insight; germline variants; hereditary colorectal cancer (CRC); indigenous african cohort; multigene panel; next generation sequencing -(NGS).

Grants and funding

This work is based on the research supported in part by the National Research Foundation of South Africa (Grant Number 143503). The study is supported by the South African Medical Research Council with funds received from the South African Department of Science and Innovation.