Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling.

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, known as colitis-associated cancer (CAC). It is still unclear what driver mutations are caused by chronic inflammation and lead to CAC development. To get insight into this issue, we investigated somatic alterations in CAC. We performed exome sequencing of 22 fresh CACs and targeted sequencing of 43 genes on 90 archive specimens from Japanese CAC patients, of which 58 were ulcerative colitis (UC) and 32 were Crohn's disease (CD). Consistently with the previous reports, was commonly mutated (66%) whereas , and were mutated less frequently (16%, 11% and 11%, respectively). Mucinous CD-CACs in the anus, an Asian-specific subtype of CD-CAC, had less somatic mutations in our target genes. We also found that , a negative regulator of the Wnt signaling, was somatically mutated in a significant fraction of CACs (10 of 90; 11%). Two lines of evidence indicated that somatic mutations of were related to chronic inflammation. First, somatic mutations of were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the -mutated CACs were actually sporadic colorectal cancer whereas -mutated CACs did not have this tendency. RNA-Seq analysis showed that -mutated CACs had elevated expression of and its target genes, suggesting that is a driver of CAC development. This study provides evidence that somatic mutation of is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs.