Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer
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 Africa...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1253867/full |
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| author | Safiye Yildiz Takudzwa N. Musarurwa Ursula Algar Ramadhani Chambuso George Rebello Paul A. Goldberg Raj Ramesar |
| author_facet | Safiye Yildiz Takudzwa N. Musarurwa Ursula Algar Ramadhani Chambuso George Rebello Paul A. Goldberg Raj Ramesar |
| author_sort | Safiye Yildiz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T15:10:06Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T15:10:06Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-bb66de43fbfb493f8fc1bc8f1b6c00d22023-10-29T17:07:18ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-10-011310.3389/fonc.2023.12538671253867Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancerSafiye Yildiz0Takudzwa N. Musarurwa1Ursula Algar2Ramadhani Chambuso3George Rebello4Paul A. Goldberg5Raj Ramesar6UCT/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 AfricaUCT/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 AfricaThe Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South AfricaUCT/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 AfricaUCT/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 AfricaThe Colorectal Unit of the Department of Surgery, Groote Schuur Hospital and the University of Cape Town, Cape Town, South AfricaUCT/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 AfricaIntroductionThe 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.https://www.frontiersin.org/articles/10.3389/fonc.2023.1253867/fullhereditary colorectal cancer (CRC)next generation sequencing -(NGS)early-onset colorectal cancergermline variantsgenetic insightindigenous african cohort |
| spellingShingle | Safiye Yildiz Takudzwa N. Musarurwa Ursula Algar Ramadhani Chambuso George Rebello Paul A. Goldberg Raj Ramesar Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer Frontiers in Oncology hereditary colorectal cancer (CRC) next generation sequencing -(NGS) early-onset colorectal cancer germline variants genetic insight indigenous african cohort |
| title | Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer |
| title_full | Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer |
| title_fullStr | Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer |
| title_full_unstemmed | Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer |
| title_short | Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer |
| title_sort | genetic insights high germline variant rate in an indigenous african cohort with early onset colorectal cancer |
| topic | hereditary colorectal cancer (CRC) next generation sequencing -(NGS) early-onset colorectal cancer germline variants genetic insight indigenous african cohort |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1253867/full |
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