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Genomic Alterations Observed in Colitis-associated Cancers are Distinct from Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease

Rona Yaeger, Manish A. Shah, Vincent A. Miller, Judith R. Kelsen, Kai Wang, Zachary J. Heins, Jeffrey S. Ross, Yuting He, Eric Sanford, Rhonda K. Yantiss, Sohail Balasubramanian, Philip J. Stephens, Nikolaus Schultz, Moshe Oren, Laura Tang, David Kelsen

Original Research Article, Gastroenterology, In Press, Accepted Manuscript, Available online 8 April 2016

Abstract
 

Background & Aims

Patients with inflammatory bowel diseases such as Crohn’s disease (CD) or ulcerative colitis (UC) are at increased risk for small bowel or colorectal cancers (colitis-associated cancers, CACs). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC.

Methods

We studied tumor tissues from patients with CACs, treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture based next-generation sequencing analysis of over 300 cancer-related genes to comprehensively characterize genomic alterations.

Results

We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n=2), right colon (n=18), left colon (n=6) and rectosigmoid or rectum (n=21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17/47 (36%) of CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC.

Conclusions

In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared to sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.

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IBD 13.03.2015

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