Clinical Impact of X-Ray Repair Cross-Complementary 1 () and the Immune Environment in Colorectal Adenoma-Carcinoma Pathway Progression.

Purpose: Colorectal cancer (CRC) can develop via a hypermutagenic pathway characterized by frequent somatic DNA base-pair mutations. Alternatively, the immunogenicity of tumor cells themselves may influence the anticancer activity of the immune effector cells. Impaired DNA repair mechanisms drive mutagenicity, which then increase the neoantigen load and immunogenicity. However, no studies have analyzed immune checkpoint protein expression, particularly programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), in adenoma-carcinoma progression and its relationship with the emergence of other DNA repair gene mutation.

Materials And Methods: We investigated mutations of 10 genes involved in DNA repair function: , and . We performed sequencing to determine mutations and immunohistochemistry of immune checkpoints in clinical samples and determined changes in expression during progression through the adenoma-carcinoma pathway. We further investigated the prognostic associations of gene according to the expression, mutational profile, and immune profile using The Cancer Genome Atlas-colon adenocarcinoma (TCGA-COAD) dataset.

Results: From clinical samples, mutation demonstrated the strongest association with adenomas with a mutation frequency of 56.2% in adenomas and 34% in CRCs (p =0.016). XRCC1 was abnormally expressed and altered by mutations contributing to adenoma carcinogenesis. High expression of XRCC1, CD4, FOXP3, and PD-1/PD-L1 showed an overall upward trend with increased lesion severity (all p < 0.01). PD-1/PD-L1 expression and CD4+ intraepithelial lymphocytes (IELs) correlated with cytological dysplasia progression, specifically in patients with wild-type (all p < 0.01), whereas FOXP3 expression was independently associated with adenoma-carcinoma progression. From TCGA-COAD analysis, expression was associated with patients survival, tumor-infiltrating lymphocytes and immune marker expression.

Conclusion: Increased IEL density and PD-1/PD-L1 expression correlate with cytological dysplasia progression and specifically with the mutation status in CRC. Our findings support a stepwise dysplasia-carcinoma sequence of adenoma carcinogenesis and an hypermutated phenotypic mechanism of lesions.