Colorectal cancers (CRCs) that evolve from inflammatory bowel disease (IBD) are genetically distinct from sporadic CRC, which may affect prognosis and treatment options, researchers say. "Strikingly, the epithelial tumor subtype most commonly seen in sporadic CRC - consensus molecular subtype (CMS) 2 - was completely absent among IBD-associated tumors," Dr. Kristiina Rajamäki of the University of Helsinki told Reuters Health by email. "These were dominated instead by a mesenchymal stroma-rich tumor subtype (CMS4) that has been previously associated with poor prognosis and drug resistance." "The findings may have implications for prognosis and treatment options of IBD-associated CRC," she said. "First treatment combinations targeting mesenchymal-like colorectal tumors have already entered clinical trials as part of the EU-funded MoTriColor project." Coauthor Dr. Toni Seppälä, also of the University of Helsinki, noted in the same email, "More information is needed on the predictive role of CMS subclasses in clinical treatment response. Distinct abnormalities in WNT signaling differentiate IBD-associated CRC from sporadic CRC, and may link the phenotypes with non-conventional precursor lesions to differences in WNT pathology." As reported in Gastroenterology, the team used whole-genome sequencing, single nucleotide polymorphism arrays, RNA sequencing, genome-wide methylation analysis, and immunohistochemistry to analyze tumor tissue and corresponding normal tissue from 31 IBD-CRC patients. As Dr. Rajamäki noted, transcriptome-based tumor subtyping showed that IBD-CRCs were mainly of the mesenchymal (non-mucosal) subtype, rather than the epithelial tumor subtype associated with WNT signaling in sporadic tumors. The analyses revealed differences between the two subtypes with regard to WNT regulators, genes involved in mucosal immunity, noncoding and somatic mutations, and other tumor characteristics. Dr. Rajamäki said, "Intriguingly, elevated intestinal expression of the oncostatin M receptor and its ligand has been associated with a subgroup of IBD patients showing poor response to TNF-alpha blockers. An interesting topic for future studies will be whether this IBD patient group is also at elevated risk for CRC." Dr. Jeffery Nelson, Surgical Director for the Center for Inflammatory Bowel and Colorectal Diseases at Mercy Medical Center in Baltimore, commented on the study in an email to Reuters Health. "We've known, or observed, for a long time that CRCs in IBD patients can look and behave differently from sporadic CRCs. They tend to be inside the wall of the colon and form strictures. They also can be more aggressive with worse prognoses." "This study points all this out and demonstrates that the genetic pathways, among other things, that lead to CRC are different in IBD patients compared to sporadic colon cancer patients," he said. "Clinically right now, it's not too impactful, because it doesn't change what we do to follow and treat IBD patients," he noted. "It does serve as another reminder that we need to be vigilant and treat IBD-related strictures of the colon as if they are cancer, until proven otherwise." "This study is more important in the realm of potential IBD-specific chemotherapy," he said. "Chemotherapeutic strategies could be developed that target the genetic pathways that lead to IBD CRC... In the future, patients with IBD-related CRCs may get different chemotherapy than patients with sporadic CRCs." —Marilynn Larkin Source
