Background: Patients (pts) 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). The genomic alterations (GA) associated with CAC have not been well-described. We hypothesized that GA associated with CAC are different than those seen with sporadic colorectal cancer (CRC). Identification of these alterations may lead to improved early detection and therapeutic options. Methods: We determined GA in 15 CAC cases confirmed as being associated with IBD at MSKCC including 11 UC and 4 CD, 14 primary and 1 metastasis (median age 55, range 29-77; 73% male). Primary tumor sites were ileum (2), right colon (5), and left colon (8). Histologic subtypes were moderately differentiated adenocarcinoma (4), mucinous (7), and signet ring/diffuse (4). Hybridization capture of the entire coding sequence of 405 cancer-related genes, including those associated with early onset IBD, was applied to DNA extracted from FFPE tumor specimens and sequenced to high, uniform coverage ( > 500x). All classes of GA including substitution, indel, copy number alteration and rearrangement were determined. Results: Potentially clinically relevant GA were identified in 8/15 CAC, including ERBB2 amplification (amp), ERBB2 S310F, EML4-ALK, FGFR2 amp, FGFR2 amp + FGFR2-TACC2 (same patient), PDGFRA T134M, and BRAF V600E + TSC2 truncation (same patient). IDH1 R132H/C were found in 2/4 CD cases (one concurrent with FGFR2 amp/fusion). Overall, 5.7 GA per tumor were detected (range 1-12). GA in TP53, the most commonly altered gene, occurred in 14/15 cases (93%; 10 known hot spot mutations), compared to 52% in CRC TCGA. KRAS and APC mutations occurred in 33% and 20%, respectively, compared to 43% and 76% in CRC TCGA. Other recurrently altered genes included SMAD4 (20%) and RNF43 (13%). Key GA associated with early onset IBD were not identified. Conclusions: Comprehensive genomic profiling identified a high frequency of potentially clinically relevant GA in CAC. GA seen in CAC suggest substantial differences from those of sporadic CRC; APC activation is infrequent and TP53 mutations are nearly universal including frequent possibly gain of function. Study of additional cases is ongoing.