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

// Masashi Fujita 1 , Nagahide Matsubara 2 , Ikuo Matsuda 3 , Kazuhiro Maejima 1 , Ayako Oosawa 1 , Tomoki Yamano 2 , Akihiro Fujimoto 4 , Mayuko Furuta 1 , Kaoru Nakano 1 , Aya Oku-Sasaki 1 , Hiroko Tanaka 5 , Yuichi Shiraishi 5 , Raul Nicolas Mateos 6, 7 , Kenta Nakai 6, 7 , Satoru Miyano 5 , Naohiro Tomita 2 , Seiichi Hirota 3 , Hiroki Ikeuchi 8 and Hidewaki Nakagawa 1 1 Laboratory for Genome Sequencing Analysis, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan 2 Division of Lower Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan 3 Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan 4 Department of Drug Discovery Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan 5 Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 6 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa-shi, Chiba, Japan 7 Laboratory of Functional Analysis in silico, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan 8 Department of Inflammatory Bowel Disease Surgery, Hyogo College of Medicine, Nishinomiya, Japan Correspondence to: Hidewaki Nakagawa, email: hidewaki@ims.u-tokyo.ac.jp Hiroki Ikeuchi, email: ikeuci2s@hyo-med.ac.jp Keywords: inflammatory bowel disease; colitis-associated cancer; next-generation sequencing; RNF43; APC Received: October 05, 2017      Accepted: November 16, 2017      Published: December 12, 2017 ABSTRACT 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, TP53 was commonly mutated (66%) whereas APC , KRAS and SMAD4 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 RNF43 , 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 RNF43 were related to chronic inflammation. First, somatic mutations of RNF43 were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the APC -mutated CACs were actually sporadic colorectal cancer whereas RNF43 -mutated CACs did not have this tendency. RNA-Seq analysis showed that RNF43 -mutated CACs had elevated expression of c-Myc and its target genes, suggesting that RNF43 is a bona fide driver of CAC development. This study provides evidence that somatic mutation of RNF43 is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs.