Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences
Abstract Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated b...
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BMC
2025-01-01
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| Series: | Hereditary Cancer in Clinical Practice |
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| Online Access: | https://doi.org/10.1186/s13053-025-00305-y |
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| author | Pål Møller Aysel Ahadova Matthias Kloor Toni T. Seppälä John Burn Saskia Haupt Finlay Macrae Mev Dominguez-Valentin Gabriela Möslein Annika Lindblom Lone sunde Ingrid Winship Gabriel Capella Kevin Monahan Daniel D. Buchanan D. Gareth Evans Eivind Hovig Julian R. Sampson |
| author_facet | Pål Møller Aysel Ahadova Matthias Kloor Toni T. Seppälä John Burn Saskia Haupt Finlay Macrae Mev Dominguez-Valentin Gabriela Möslein Annika Lindblom Lone sunde Ingrid Winship Gabriel Capella Kevin Monahan Daniel D. Buchanan D. Gareth Evans Eivind Hovig Julian R. Sampson |
| author_sort | Pål Møller |
| collection | DOAJ |
| description | Abstract Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage. |
| format | Article |
| id | doaj-art-b702c23d35464edfa6d375b88a6e5ad3 |
| institution | Kabale University |
| issn | 1897-4287 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Hereditary Cancer in Clinical Practice |
| spelling | doaj-art-b702c23d35464edfa6d375b88a6e5ad32025-01-26T12:54:56ZengBMCHereditary Cancer in Clinical Practice1897-42872025-01-012311710.1186/s13053-025-00305-yColorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequencesPål Møller0Aysel Ahadova1Matthias Kloor2Toni T. Seppälä3John Burn4Saskia Haupt5Finlay Macrae6Mev Dominguez-Valentin7Gabriela Möslein8Annika Lindblom9Lone sunde10Ingrid Winship11Gabriel Capella12Kevin Monahan13Daniel D. Buchanan14D. Gareth Evans15Eivind Hovig16Julian R. Sampson17Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital Oslo University HospitalDepartment of Applied Tumour Biology, Institute of Pathology, Heidelberg University HospitalDepartment of Applied Tumour Biology, Institute of Pathology, Heidelberg University HospitalFaculty of Medicine and Health Technology, Tays Cancer Centre, Applied Tumor Genomics Research Program, Research Programs Unit, Tampere University, Tampere University Hospital, University of HelsinkiFaculty of Medical Sciences, Newcastle UniversityDepartment of Applied Tumour Biology, Institute of Pathology, Heidelberg University HospitalColorectal Medicine and Genetics, The Royal Melbourne HospitalDepartment of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital Oslo University HospitalSurgical Center for Hereditary Tumors, University Witten-HerdeckeDepartment of Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Clinical Genetics and Clinical Cancer Research Center, Aalborg University HospitalGenomic Medicine, The Royal Melbourne HospitalHereditary Cancer Program, Institut Català d’Oncologia-IDIBELL, L; Hospitalet de LlobregatCentre for Familial Intestinal Caner, Lynch Syndrome & Family Cancer Clinic, St Mark’s HospitalColorectal Oncogenomics Group, Department of Clinical Pathology, The University of MelbourneManchester Centre for Genomic Medicine, Division of Evolution, Infection and Genomic Sciences, University of Manchester, Manchester University NHS Foundation TrustDepartment of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital Oslo University HospitalDivision of Cancer and Genetics, Cardiff University School of MedicineAbstract Carcinogenesis encompasses processes that lead to increased mutation rates, enhanced cellular division (tumour growth), and invasive growth. Colorectal cancer (CRC) carcinogenesis in carriers of pathogenic APC (path_APC) and pathogenic mismatch repair gene (path_MMR) variants is initiated by a second hit affecting the corresponding wild-type allele. In path_APC carriers, second hits result in the development of multiple adenomas, with CRC typically emerging after an additional 20 years. In path_MLH1 and path_MSH2 carriers, second hits lead to the formation of microscopically detectable, microsatellite unstable (MSI) crypts, from which CRC develops in about half of carriers over their lifetime, often without progressing through a diagnosable adenoma stage. These divergent outcomes reflect the distinct functions of. the APC and MMR genes. In path_MLH1 and path_MSH2 carriers, a direct consequence of stochastic mutations may be the occurrence of invasive growth before tumour expansion, challenging the paradigm that an invasive cancer must always have an non-invasive precursor. In contrast to other path_ MMR carriers, path_PMS2 carriers who receive colonoscopic surveillance exhibit minimal increase in CRC incidence. This is consistent with a hybrid model: the initial mutation may cause an adenoma, and the second hit in the wild-type PMS2 allele may drive the adenoma towards become cancerous with MSI. Since all mutational events are stochastic, interventions aimed at preventing or curing cancer should ideally target the initial mutational events. Interventions focused on downstream events are external factors that influence which tumour clones survive Darwinian selection. In Lynch Syndrome, surveillance colonoscopy to remove adenomas may select for carcinogenetic pathways that bypass the adenoma stage.https://doi.org/10.1186/s13053-025-00305-yInheritedCancerColorectalLynch syndromesLSMSI |
| spellingShingle | Pål Møller Aysel Ahadova Matthias Kloor Toni T. Seppälä John Burn Saskia Haupt Finlay Macrae Mev Dominguez-Valentin Gabriela Möslein Annika Lindblom Lone sunde Ingrid Winship Gabriel Capella Kevin Monahan Daniel D. Buchanan D. Gareth Evans Eivind Hovig Julian R. Sampson Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences Hereditary Cancer in Clinical Practice Inherited Cancer Colorectal Lynch syndromes LS MSI |
| title | Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences |
| title_full | Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences |
| title_fullStr | Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences |
| title_full_unstemmed | Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences |
| title_short | Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences |
| title_sort | colorectal carcinogenesis in the lynch syndromes and familial adenomatous polyposis trigger events and downstream consequences |
| topic | Inherited Cancer Colorectal Lynch syndromes LS MSI |
| url | https://doi.org/10.1186/s13053-025-00305-y |
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