Background: Patients with inflammatory bowel disease (IBD) [Crohn’s disease (CD) and ulcerative colitis (UC)] are at increased risk for small bowel or colorectal cancers (Colitis Associated Cancers, CAC). Currently CAC is treated the same as sporadic colorectal cancer (CRC) with significantly shorter overall survival for advanced CAC compared to matched patients with CRC. In a pilot series, we found that tumors developing in IBD have distinct genomic alterations (GA) with potential implications for early detection and treatment. We now extend this analysis and characterize the relationship of GA in synchronous dysplasia and cancer. Methods: 104 CAC (54 UC-associated and 50 CD-associated) were sequenced with targeted-exome sequencing of > 300 cancer-related genes. GA in CAC were compared to those reported for sporadic CRC. Whole exome sequencing was performed on paired mucosa, dysplasia and carcinoma samples obtained from 15 colectomy specimens; in these cases, expert pathology review confirmed normal appearing mucosa intervening between areas of dysplasia and CAC. Results:TP53 mutations (89%), MYC amplifications (24%), and cell cycle copy number alterations (20%) were significantly enriched in CAC compared to sporadic CRC, while APC alterations (21%) were significantly less common in CAC compared to sporadic CRC. Distinct GA in CAC consisted of IDH1R132 mutations (7%) and FGFR pathway alterations (7%). While IDH1R132 mutations and PI3K pathway alterations were more common in CD-associated CAC, MAPK (BRAF/MEK1) alterations were more common in UC-associated CAC. GA in CACs did not significantly vary by duration of preceding IBD. GA were often shared in dysplasia and carcinoma, despite normal-appearing intervening mucosa. GA involving TP53, APC, KRAS, and IDH1 mutations were identified in dysplasia and shared between CAC and dysplasia. Conclusions: CAC exhibit distinct GA compared to sporadic CRC with near universal TP53 mutation, increased copy number alterations involving transcription factors and cell cycle genes, and unique drivers. A field effect can be seen for GA between distant dysplasia and carcinoma, but many GA remain private to CAC.