Aysel Ahadova1,2,3,4, Richard Gallon1,5, Johannes Gebert2,3,4, Alexej Ballhausen2,3,4, Volker Endris6, Martina Kirchner6, Albrecht Stenzinger6, John Burn5, Magnus von Knebel Doeberitz2,3,4, Hendrik Bläker7, Matthias Kloor2,3,4
1A.A. and R.G. contributed equally to the manuscript.
2Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3Department of Applied Tumor Biology, Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
4Molecular Medicine Partnership Unit (MMPU), University Hospital Heidelberg, Heidelberg, Germany
5Institute of Genetic Medicine, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, United Kingdom
6Department of General Pathology, Institute of Pathology, University Hospital Heidelberg Im Neuenheimer Feld 224, Heidelberg, 69120 Germany
7Department of General Pathology University Hospital Charité, Charitéplatz 1 Berlin 10117 Germany
Tóm tắt
Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR‐deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR‐deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR‐deficient cells by chemoprevention or vaccines against MMR deficiency‐induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome.
