A DNA damage response-like phenotype defines a novel subset of colon cancer

Abstract Colon adenocarcinoma (COAD) has a limited range of diversified, personalized therapeutic opportunities, besides DNA hypermutating cases; thus both new targets or broadening existing strategies for personalized intervention are of interest. Routinely processed material from 246 untreated COADs with clinical follow-up was probed for evidence of DNA damage response (DDR) by multiplex immunofluorescence and immunohistochemical staining for DDR complex proteins (ℽH2AX, pCHK2, pNBS1) and for type I interferon response, T-lymphocyte infiltration (TILs), mutation mismatch repair defects (MMRd). FISH analysis for chromosome 20q copy number variations was obtained. 33.7% of COAD display a coordinated DDR on quiescent, non-senescent, non-apoptotic glands, irrespective of TP53, chromosome 20q abnormalities, type I IFN response. Clinicopathological parameters did not differentiate DDR + cases from the other cases. TILs were equally present in DDR and non-DDR cases. DDR + MMRd cases were preferentially retaining wild-type MLH1. The outcome after 5FU-based chemotherapy was not different in the two groups. DDR + COAD represents a subgroup not aligned with known diagnostic, prognostic or therapeutic categories, with potential new targeted treatment opportunities.