Genomic Alterations Observed in Colitis-Associated Cancers Are Distinct From Those Found in Sporadic Colorectal Cancers and Vary by Type of Inflammatory Bowel Disease

Abstract

Background & aims: Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and 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 >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 of 47 (36%) 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 with 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.

Keywords: Bowel Cancer; Cancer of the Ileum; IBD; Inflammatory Bowel Disease.

Figure 1

Oncoprint showing genes mutated in at least 10% of CAC cases. Each column denotes an individual tumor and each row represents a gene. Colors indicate type of genomic alteration as indicated in the legend below the oncoprint.

Figure 2

Comparative analysis of the frequency of alterations in recurrently altered genes in Colitis-Associated Cancers (CAC) and in sporadic colorectal cancer. Top: Table showing the frequency of alterations in the indicated genes in the CAC cases overall (UC-associated plus CD-associated) versus the frequency of alterations in the same genes as found in the TCGA-CRC, and in the Foundation Medicine database (FM-CRC), and associated p-values based on Fisher's exact test. Bottom: Bar graph showing the relative frequency of genomic alterations in the indicated genes in CAC associated with UC (UC-CAC), CAC associated with CD (CD-CAC), TCGA-CRC, and FM-CRC. Differences in the frequency of alterations that were statistically significant, based on Fisher's exact test, are indicated with a star.

Figure 3

Photomicrograph of rectal mucosa adjacent to tumor that shows no active colitis in a patient with history of quiescent CD and a tumor genomic alterations analysis mutation profile consistent with sporadic CRC. The horizontal sizing bar indicates 500um.

Figure 4

Photomicrographs of colon mucosa showing (A) transmural chronic colitis and (B) granuloma formation (arrow), histologic changes characteristic of Crohn's colitis, in a patient with clinical history of UC, but found to have tumor IDH1 R132 mutation. The horizontal sizing bars indicate 500um.

Figure 5

Oncoprint showing alterations in genes that are potentially actionable, defined as genes whose altered product can be targeted either by agents that are already FDA-approved for other indications or are currently in clinical trials. Each column denotes an individual tumor and each row represents a gene. Colors and symbols indicate type of genomic alteration as indication in the legend below the oncoprint.

Figure 6

Pathway alterations diagram integrating gene mutations and copy number alterations to identify pathways altered in UC- and CD-associated CAC. Alteration frequencies are expressed as a percentage of CD-associated cases (left side of box) and of UC-associated cases (right side of box). Red denotes activated genes and blue denotes inactivated genes, with the brightness of these colors corresponding to the percentage of cases altered. Amplifications and missense mutations in recurrent positions in oncogenes were considered activating, and deletions, truncating mutations as well as recurrent missense mutations in tumor suppressor genes were considered inactivating.