Colorectal carcinogenesis in the Lynch syndromes and familial adenomatous polyposis: trigger events and downstream consequences
Year: 2025
Type: review
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.
Institutions: Oslo University Hospital, University Hospital Heidelberg, University of Helsinki, Tampere University, Helsinki University Hospital, Tampere University Hospital, Newcastle University, The Royal Melbourne Hospital, The University of Melbourne, Witten/Herdecke University, Karolinska University Hospital, Karolinska Institutet, Aarhus University, Aalborg University Hospital, Institut d'Investigació Biomédica de Bellvitge, Institut Català d'Oncologia, St Mark's Hospital, Victorian Comprehensive Cancer Centre, University of Manchester, Manchester University NHS Foundation Trust, Cardiff University
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,690
OpenAlex ID: W4406767632