Genomic landscape of colorectal carcinoma in sub-Saharan Africa

Aldera, Alessandro Pietro; Pillay, Komala; Robertson, Barbara; Boutall, Adam; Ramesar, Raj

doi:10.1136/jcp-2022-208482

Cited by 3 publications

(1 citation statement)

References 49 publications

(75 reference statements)

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“…Notably, in sub-Saharan Africa, the prevalence of CRC is increasing predominantly in young individuals below the age of 40 years especially in indigenous African patients (6)(7)(8)(9). Most importantly, comprehensive cancer genetics in early age of onset (eAOO) CRC has not yet been investigated in the indigenous African population despite their increasing prevalence and greater aggressiveness than in non-African populations (10). This presents a public-health problem in cancer genetics.…”

Section: Introductionmentioning

confidence: 99%

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

Yildiz,

Musarurwa,

Algar

et al. 2023

Front. Oncol.

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IntroductionThe 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 methodsPatients 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.ResultsOut 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.ConclusionThe 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.

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Section: Introductionmentioning

confidence: 99%

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

Yildiz,

Musarurwa,

Algar

et al. 2023

Front. Oncol.

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Chemical-chemical redox cycling for improving the sensitivity of the fluorescent assay: A proof-of-concept towards DNA methylation detection

Zhang,

Wu,

Xiao

et al. 2024

Talanta

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Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa

Aldera,

van der Westhuizen,

Tsai

et al. 2024

J Clin Pathol

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AimsColorectal 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.Methods32 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).ResultsPathogenic 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 inMLH1(three) andMSH2(one). Cases with a variant allele frequency suggesting a germline mutation were identified inMLH1(eight),MSH2(two) andMSH6(one). Only one MMR gene variant was detected in more than one patient (MLH1p.Q510*). FourPOLE/POLD1exonuclease domain variants were identified, one of which was previously unreported.ConclusionThe 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.

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Genomic landscape of colorectal carcinoma in sub-Saharan Africa

Cited by 3 publications

References 49 publications

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

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

Chemical-chemical redox cycling for improving the sensitivity of the fluorescent assay: A proof-of-concept towards DNA methylation detection

Investigating somatic variants and pathways in mismatch repair-deficient (dMMR) colorectal carcinoma in South Africa

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