N52: MMR Deficiency Is An Early Event In Lynch Syndrome Colorectal Cancer Pathogenesis

A. Ahadova1, R. Gallon3, J. Gebert2, A. Ballhausen2, V. Endris2, M. Kirchner2, A. Stenzinger2, J. Burn3, M. von Knebel Doeberitz2, H. Bläker4, M. Kloor2

1 – Department of Applied Tumor Biology, University Hospital Heidelberg. 2 – University Hospital Heidelberg. 3 – Newcastle University. 4 – Charite Berlin.

 

Aim: The onset of mismatch repair (MMR) deficiency in Lynch syndrome-associated tumors has been discussed to be a late event of pathogenesis. Since the time point of MMR deficiency onset and its consequences have a direct impact on the selection of suitable therapeutic and preventive measures, we aimed to reconstruct the sequence of mutational events in Lynch syndrome cancers.

Method: MMR protein expression and mutational signatures were analyzed to address the time point of MMR deficiency in Lynch syndrome adenomas and carcinomas from public databases and our own cohort.

Results: 77% of Lynch syndrome adenomas (n=640) were MMR-deficient. Mutational signatures of MMR deficiency were reflected in canonical CRC gene mutations, demonstrating that 100% of KRAS and more than 60% of APC mutations likely occurred after the onset of MMR deficiency. A substantial proportion of Lynch syndrome-associated colorectal cancers lacked evidence of polypous growth. These tumors showed a distinct molecular pattern enriched for TP53 and CTNNB1 mutations.

Conclusion: There is more than one pathway of CRC development in Lynch syndrome. MMR deficiency commonly occurs early during Lynch colorectal carcinogenesis. Non-polypous cancers developing from MMR-deficient crypts may be missed by colonoscopy, strengthening the need for additional primary prevention measures in Lynch syndrome.

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