Colitis-associated cancers differ from sporadic colorectal cancers

Last Updated: 2016-04-22

By Marilynn Larkin

NEW YORK (Reuters Health) - Genomic data show differences between colitis-associated cancers and sporadic colorectal cancers and between those associated with Crohn's disease and ulcerative colitis (UC), researchers report.

"Patients with inflammatory bowel disease (IBD) are at a substantially increased risk for cancers of the colon/rectum or (for Crohn's disease) the small bowel, and the risk increases the longer IBD is active," Dr. David Kelsen of Memorial Sloan Kettering Cancer Center in New York City and colleagues write in Gastroenterology, online April 7.

"Colitis-associated cancers (CAC) are an especially feared complication of IBD, as they are frequently diagnosed at an advanced stage, with locally advanced or metastatic disease. Unlike more common sporadic colorectal cancers (CRC) that arise from polyps, it may be difficult to identify pre-cancerous dysplastic lesions or early CAC in patients with IBD," they note.

To characterize the genomic alterations in CAC that are potentially targetable by drug therapy, the researchers performed genomic analyses on CACs from 29 patients with UC and 18 with Crohn's disease (CD), including 43 primary tumors and four metastases.

Genomic alterations in TP53, IDH1 and MYC were significantly more frequent, and mutations in APC were significantly less frequent than those reported in sporadic CRCs in The Cancer Genome Atlas and the Foundation Medicine database, according to the authors.

"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," they write, concluding that "many genetic alterations observed in CACs could serve as therapeutic targets."

"In summary, our data support the hypothesis that CAC is a biologically different malignancy from sporadic CRC," Dr. Kelsen told Reuters Health by email. "A better understanding of the genomic events underlying the development of CAC could have implications for early detection of CAC in patients with IBD and for new therapeutic options for more advanced CAC."

"Different TP53 mutations may confer a different risk profile for the development of frank carcinoma in dysplastic lesions," he explained. "The identification of 'second genomic hits' in dysplastic lesions, the majority of which already have TP53 mutations, may also serve as biomarkers guiding management."

"For example, the identification of either an activating TP53 mutation or a second genomic event in a dysplastic lesion may guide the extent of regional intervention - e.g., surgical resection instead of endoscopic mucosal resection," he continued. "Further, our data suggest that there may be a spectrum of differences in genomic alterations between UC and CD cases, and raise the possibility that an IDH1 mutation may be both a marker for CD-associated CAC and a promising therapeutic target."

"Systemic therapy for CAC given as adjuvant or palliative treatments uses the same treatment plans as for 'sporadic' colorectal cancers. Our study and other recent research provides strong evidence that the genomic events in CAC are different than those of more common colorectal cancers, suggesting that CAC treatment options may also be different from those used in CRC," he said.

"We also show that the type of IBD is associated with different genomic alterations profiles, suggesting further that early detection and treatment might be tailored to the IBD subtype."

Dr. Kelsen and his colleagues are currently trying to identify additional genomic changes that could function as drivers of the malignant process, he said.

"We have initiated a patient-derived xenograft project to test, in a mouse model, novel agents targeting the specific mutations in an individual patient's own CAC tumor, allowing a precision medicine approach to guide therapy in that patient. In addition, we will use the genomic alterations we have already identified to develop new tests for early detection of CAC in IBD patients," Dr. Kelsen concluded.

Dr. Steven H. Itzkowitz, director of the Gastroenterology Fellowship Program at the Icahn School of Medicine at Mount Sinai in New York City, commented by email that the new findings "can be summarized as three observations: 1) there were some differences in the spectrum of genomic alterations between CACs and sporadic cancers; 2) certain genes (particularly IDH1) were expressed more in Crohn's disease than UC-associated cancer; and 3) about a third of CACs had genomic alterations that might be potential targets for known therapeutic agents."

"While the first observation confirms previous findings, the second and third observations offer novel insights into potentially new approaches to diagnosing and perhaps treating CACs," he continued. "It will be interesting to see if these findings will be replicated in other CAC cases, and whether any of the so-called actionable therapeutic targets might be effective. The fact that only a minority of CACs demonstrate these somewhat unique features means that more work needs to be done, but (this) study provides a useful start."

The study was supported by grants from the National Institutes of Health and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

SOURCE: http://bit.ly/1SzQSAb

Gastroenterology 2016.