Genomic Landscape of Early-stage Colorectal Neoplasia Developing From the Ulcerative Colitis Mucosa in the Japanese Population

Abstract

Backgrounds: Colorectal neoplasias (CRN)s developing from the ulcerative colitis (UC) mucosa include both colitic and sporadic neoplasias. Although several genomic analyses of advanced colitis-associated cancer are available, such studies do not distinguish between colitic and sporadic cases, and the early-stage genomic alterations involved in the onset of colitic cancer remain unclear. To address this, we performed a genomic analysis of early-stage CRN developing from the UC mucosa (CRNUC).

Methods: We extracted DNA from 36 early-stage CRNUCs (T1 cancer, 10; dysplasia, 26) from 32 UC patients and performed targeted sequencing of 43 genes commonly associated with colitis-associated cancer and compared the results with sequencing data from the Japanese invasive colitis-associated cancer.

Results: The most frequently mutated gene in the CRNUC cohort was APC (mutated in 47.2% of the cases), followed by TP53 (44.4%), KRAS (27.8%), and PRKDC (27.8%). None of the TP53 mutations occurred at any of the hotspot codons. Although the TP53 mutations in The Cancer Genome Atlas of Colorectal Cancer were dispersed throughout the gene, those detected here in CRNUC cases were concentrated in the amino terminal part of the DNA-binding domain. Interestingly, the mutations in KRAS and TP53 were mutually exclusive in CRNUC, and CRNUCs with KRAS mutations had histologically serrated lesions in the gland duct. Mayo endoscopic subscore was higher in TP53-mutated CRNUCs and lower in KRAS-mutated CRNUCs.

Conclusions: Our findings suggest that early-stage CRNUC can be classified into 2 groups: those developing through the carcinogenic pathway via TP53 mutations and those developing through the carcinogenic pathway via KRAS mutations.

Keywords: KRAS; TP53; UC; colitic neoplasia; sporadic neoplasia; ulcerative colitis.