Abstract 127: The genomic landscapes of inflammatory bowel disease-associated colorectal cancers
Authors: Robles Ana I. , Traverso Giovanni , Zhang Ming , Roberts Nicholas , Khan Mohammed A. , Joseph Christine , Lauwers Gregory , Selaru Florin , Popoli Maria , Ke Xiquan , Hruban Ralph H. , Meltzer Stephen J. , Kinzler Kenneth W. , Vogelstein Bert , Harris Curtis C. , Papadopoulos Nickolas 
Published: July 2016

Long duration inflammatory bowel disease (IBD) increases the risk for colorectal cancer (CRC). Mutation analysis of limited numbers of genes has suggested that CRCs arising in an IBD background differ from those that do not. We sought to characterize the genetic landscape of these tumors through whole-exome sequencing.

Thirty-one IBD patients with CRC were identified, including 15 with ulcerative colitis, 14 with Crohn's disease and 2 with indeterminate colitis. Whole-exome sequencing was performed on micro-dissected tumor and matched non-neoplastic formalin-fixed paraffin-embedded (FFPE) tissues. Somatic alterations were identified by comparing matched specimens. Mutation prevalence in sporadic CRC was obtained from previously published exome-sequencing studies.

An average of 11.6 Gb were sequenced per sample. The depth of quality coverage of the targeted region was 29 to 100-fold in the tumors; and 17- to 123-fold in non-tumor samples. Two specimens harbored somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1 and MSH6 and exhibited hypermutable phenotype. The remaining cases had a median mutation rate of 1.33 mutations/Mb and an average of 71 alterations per sample. The pattern of base changes in non-hypermutated tumors showed a preponderance of C to T transitions (62%), a majority of which (48% of all mutations) occurred at 5′-CpG-3′ sites. An excess of A to C transversions at AA dinucleotides, particularly in a context of AAG trinucleotides, was also noted. This pattern has been previously observed in esophageal and gastric cancers, both of which are also tied to chronic inflammation. There were no apparent differences in the spectrum of substitutions between tumors arising in UC and CD patients. We identified 28 genes recurrently mutated in three or more non-hypermutated samples. TP53 was the most commonly mutated gene, with incidence prevalence similar to sporadic CRC (63% of cases), but with different mutation spectrum. APC and KRAS were mutated at significantly lower rates than in sporadic CRCs (13% and 20% of cases, respectively). Genes mutated more commonly or uniquely in IBD-CRC, included SOX9 and EP300, encoding proteins in the WNT pathway, NRG1, encoding an ERBB ligand, and IL16, encoding a cytokine. Three cases featured hotspot PIK3CA mutations. Likely oncogenic driver gene mutations in BRAF, CTNNB1, and CREBBP were found in one case each. Mutated genes were enriched for gene ontologies associated with cell communication, cell-cell signaling, and cell adhesion. Our study also revealed recurrent mutations in components of the Rho/Rac GTPase network, suggesting a role for non-canonical WNT signaling in IBD-CRC.

CRCs arising in IBD patients demonstrate a unique molecular profile, which provides clues to their etiology. Our study also sets the stage for improved early detection of IBD-associated CRCs based on their unique genetic compositions as well as for the tailoring of therapies in this patient population.

Citation Format: Ana I. Robles, Giovanni Traverso, Ming Zhang, Nicholas Roberts, Mohammed A. Khan, Christine Joseph, Gregory Lauwers, Florin Selaru, Maria Popoli, Xiquan Ke, Ralph H. Hruban, Stephen J. Meltzer, Kenneth W. Kinzler, Bert Vogelstein, Curtis C. Harris, Nickolas Papadopoulos. The genomic landscapes of inflammatory bowel disease-associated colorectal cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 127.