Abstract
Immunological and epigenetic changes are interconnected and contribute to tumorigenesis. We determined the immunoprofiles and promoter methylation of inflammation-related genes for colitis-associated colorectal carcinomas (CA-CRC). The results were compared with Lynch syndrome (LS)-associated colorectal tumors, which are characterized by an active immune environment through inherited mismatch repair defects. CA-CRCs (n = 31) were immunohistochemically evaluated for immune cell scores (ICSs) and PDCD1 and CD274 expression. Seven inflammation-associated genes (CD274, NTSR1, PPARG, PTGS2, PYCARD, SOCS1, and SOCS2), the repair gene MGMT, and eight standard marker genes for the CpG Island Methylator Phenotype (CIMP) were investigated for promoter methylation in CA-CRCs, LS tumors (n = 29), and paired normal mucosae by multiplex ligation-dependent probe amplification. All but one CA-CRCs were microsatellite-stable and all LS tumors were microsatellite-unstable. Most CA-CRCs had a high ICS (55%) and a positive CD274 expression in immune cells (52%). NTSR1 revealed frequent tumor-specific hypermethylation in CA-CRC and LS. When compared to LS mucosae, normal mucosae from patients with CA-CRC showed significantly higher methylation of NTSR1 and most CIMP markers. In conclusion, CA-CRCs share a frequent ICShigh/CD274pos expression pattern with LS tumors. Elevated methylation in normal mucosa may indicate field cancerization as a feature of CA-CRC-associated tumorigenesis.
Highlights
Lynch syndrome (LS) samples, NTSR1, SOCS2, and SOCS1 showed tentatively increased methylation frequencies in carcinomas compared to normal mucosae, but only NTSR1 remained significant after adjustment for multiple testing (p = 0.037) (Figure 4b)
Among LS samples, NTSR1, SOCS2, and SOCS1 showed tentatively increased methylation frequencies in carcinomas compared to normal mucosae, but only NTSR1 remained significant after adjustment for multiple testing (p = 0.037) (Figure 4b)
Many key cytokines and transcription factors required for the differentiation and function of central component cells of innate andrequired adaptivefor immunity are epigenetically
Summary
LS is the most common hereditary condition predisposing to CRC and is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2 [8] or, more rarely, deletions in the 30 end of the EPCAM gene, leading to hypermethylation of the MSH2 gene promoter [9] These heterozygous germline defects decrease the levels of functional MMR proteins, compromising their critical cancer avoidance functions and resulting in hypermutated and microsatellite-unstable tumors [10,11]. Available information of immune cell infiltration in CA-CRC is limited, and the findings are in part conflicting [17,18,19] As these observations imply, inflammation has an important role in cancer; epigenetic regulation of inflammation-associated genes and its impact on UC- and LSassociated CRC tumorigenesis are not completely understood. We aimed ate the immunological landscape of CA-CRCs through ICS and altered methylation of inflammation-associated genes, using LS tumors for comparison (Figure 1)
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