Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer
Challoner, B. R.; Woolston, A.; Lau, D.; Buzzetti, M.; Fong, C.; Barber, L. J.; Anandappa, G.; Crux, R.; Assiotis, I.; Fenwick, K.; Begum, R.; Begum, D.; Lund, T.; Sivamanoharan, N.; Sansano, H. B.; Domingo-Arada, M.; Tran, A.; Eccles, B.; Ellis, R.; Falk, S.; Hill, M.; Krell, D.; Murugaesu, N.; Nolan, L.; Potter, V.; Saunders, M.; Shiu, K.-K.; Guettler, S.; Alexander, J. L.; Lazare-Iglesias, H.; Kinross, J.; Murphy, J.; von Loga, K.; Cunningham, D.; Chau, I.; Starling, N.; Ruiz-Banobre, J.; Dhillon, T.; Gerlinger, M.
Show abstract
Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/{beta}Catenin, mitogen-activated protein kinase and TGF{beta} receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.
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