Routes to colorectal cancer in Lynch syndrome: a decade of molecular and clinical insights converging on Schrödinger's cat.

Authors

Aysel Ahadova, Fatima Fayyaz, Leon Marin Grez, Hendrik Bläker, Matthias Kloor

Published in

Familial cancer. Volume 25. Issue 3. Aug 04, 2026. Epub Aug 04, 2026.

Abstract

Colorectal cancer (CRC) development in Lynch syndrome (LS) has long been regarded to follow an adenoma-carcinoma sequence accelerated in comparison to microsatellite-stable (MSS) CRC development. 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.

PMID:
42550307
Bibliographic data and abstract were imported from PubMed on 04 Aug 2026.

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