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Yet, several clinical observations challenged this hypothesis, most notably the persistently high CRC incidence under colonoscopy surveillance, a non-measurable benefit from shorter screening intervals, and substantial differences in cancer risk between carriers of the different mismatch repair (MMR) genes. Advances in the last decade have produced new hypotheses, highlighting the distinct biology of LS CRC and unravelling several co-existing pathways to cancer. Alongside the genomic heterogeneity, the immunogenic load created by the accumulation of frameshift mutations imposing selective pressure and leading to immune evasion, appears to be a critical step for cancer manifestation. We discuss potential clinical implications of these advances in understanding CRC pathogenesis for cancer prevention in LS and outline open questions that remain.<\/jats:p>","DOI":"10.1007\/s10689-026-00593-w","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T06:50:52Z","timestamp":1785826252000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Routes to colorectal cancer in Lynch syndrome: a decade of molecular and clinical insights converging on Schr\u00f6dinger\u2019s cat"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9890-0450","authenticated-orcid":false,"given":"Aysel","family":"Ahadova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Fayyaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon","family":"Marin Grez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik","family":"Bl\u00e4ker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Kloor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"issue":"6","key":"593_CR1","doi-asserted-by":"publisher","first-page":"2044","DOI":"10.1053\/j.gastro.2010.01.054","volume":"138","author":"KW Jasperson","year":"2010","unstructured":"Jasperson KW et al (2010) Hereditary and familial colon cancer. 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