Expression Of Proteins Involved In Carcinogenic Pathways In Patients With Primary Sclerosing Cholangitis And Colitis-Associated Colorectal Cancer

Background : The molecular background of colitis-associated carcinogenesis differs from the sporadic pathway in frequency and moment of underlying genetic mutations. Patients with IBD and concurrent primary sclerosing cholangitis (PSC) have a significantly higher risk of developing colorectal cancer (CRC) than patients without PSC. Although themolecular background behind colorectal carcinogenesis is gradually elucidated, still little is known about this specific subgroup of tumors. Aim : To compare the expression of proteins involved in different carcinogenic mechanisms in PSC-IBD-related CRC with other subtypes of colorectal tumors, such as IBD-CRC, sporadic CRC and Lynch syndrome-related CRC, and to determine differences in the molecular background of inflammatoryand noninflammatory-associated CRCs. Methods : A tissue micro-array was constructed with colonic samples from 7 groups: (1) healthy subjects, (2) IBD-patients, (3) IBD-related CRC, (4) PSC-IBD-related CRC, (5) Lynch syndrome-related CRC, (6) sporadic left-sided CRC, and (7) sporadic right-sided CRC. Each group consisted of 8-20 patients. Immunohistochemistry was performed using monoclonal antibodies against β-catenin, Cylin D1, CD44V6, p53, SMAD4, and COX2. Results : Median age of all patients was 55 years (range 12-92 years), with 61% of cases being male. Of all cases in groups 2-4, ulcerative colitis was present in 53% of cases. In groups 3, 4 and 5, 29%, 60%, and 50% of CRCs, respectively, were proximally located, (p=0.3). In 55.4% of all tumors, CRC had metastasized to regional lymph nodes or distant sites. Overexpression of p53 was found in the majority of all tumors (60%), except the Lynch-CRC group (12.5%) (p=0.44). Expression of Cyclin D1 was found in 56% and 88% of the inflammatory-related tumors and sporadic tumors, respectively (p= 0.002). After correction for tumor stages and age this difference remained significant. No statistical differences were found in expression of nuclear β-catenin, CD44V6, and COX-2. Loss of expression of SMAD4 was twice as high in the inflammatory-related tumor groups compared to the sporadic tumors, 26% and 9%, respectively (p=0.09). No association was found between the expression of β-catenin andCyclin D1.Conclusion : Cyclin D1 expression is significantly less in the inflammatory-related tumor group than in the sporadic CRCs and there appears to be loss of SMAD4 expression as well: this suggests a difference in colorectal carcinogenesis between these two groups.