Molecular markers of carcinogenesis for risk stratification of individuals with colorectal

Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer (CRC). We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n=216; 46% female) in which cases were patients with CRC and synchronous adenoma and controls were patients with adenoma but no CRC at baseline or within 5 years of follow-up. In phase I of analyses, we compared expression of molecular markers of carcinogenesis in case and control adenomas, blind to case status. In phase II of analyses, patients were randomly divided into independent training and validation groups to develop a model for predicting case status. We found that seven markers (p53, p21, Cox-2, beta-catenin, DNA dependent protein kinase (DNApkcs), survivin, and 0(6)-methylguanine-DNA methyltransferase (MGMT)) were significantly associated with case status on unadjusted analyses, as well as analyses adjusted for age and advanced adenoma status (p<0.01 for at least one marker component). When applied to the validation set, a predictive model using these 7 markers showed substantial accuracy for identifying cases (AUC=0.83; 95% CI:0.74-0.92). A parsimonious model employing 3 markers performed similarly to the 7 marker model (AUC=0.84). In summary, we found that molecular markers of carcinogenesis distinguished adenomas from patients with and without CRC. Cancer Research. on April 2, 2017. © 2014 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on August 4, 2014; DOI: 10.1158/1940-6207.CAPR-14-0140