ORIGINAL CONTRIBUTION Divergent Oncogenic Changes Influence Survival Differences between Colon and Rectal Adenocarcinomas Matthew F. Kalady, M.D. 1,2 & Julian A. Sanchez, M.D. 1 & Elena Manilich, M.S. 1 Jeff Hammel, M.S. 1 & Graham Casey, Ph.D. 2 & James M. Church, M.B., Ch.B. 1 1 Department of Colorectal Surgery, Cleveland Clinic, Cleveland, Ohio 2 Department of Cancer Biology, Cleveland Clinic, Cleveland, Ohio PURPOSE: Colorectal cancers develop through various mechanisms such as chromosomal instability, DNA mismatch repair deficiency (microsatellite instability), and epigenetic DNA promoter methylation (CpG island methylator phenotype). This study evaluated the disparity in neoplastic changes between colon and rectal cancers. METHODS: A clinic-based colorectal frozen tumor bank at a single institution was queried for colon and rectal adenocarcinomas. Tumor DNA was extracted and analyzed for microsatellite instability, methylation, and mutations in the oncogenes KRAS and BRAF. Patient demographics, tumor characteristics, and clinical outcomes were compared. RESULTS: The 268 patients with colon cancer and 89 with rectal cancer were similar in gender, tumor size, stage, and differentiation. Colon cancers had a higher incidence of microsatellite instability (27 percent) and methylator phenotype (28 percent) compared with rectal cancers (7 percent, 3 percent, respectively; P G 0.001). Although KRAS mutation rate was similar, colon cancers had a higher incidence of BRAF mutations (16.7 percent vs. 0 percent; P G 0.001). Microsatellite stable tumors had an increased risk of disease recurrence compared with microsatellite unstable tumors (odds ratio, 3.86). Despite overall differences in outcome between colon and rectal cancers, no significant difference in survival existed when similar molecular phenotypes were compared across anatomic sites. CONCLUSIONS: Although colon cancers are molecularly heterogeneous, rectal cancers arise mostly via a single neoplastic pathway. Genetic and molecular differences influence prognosis more than anatomic location and suggest that oncogenic pathways contribute to survival differences between colon and rectal cancers. KEY WORDS: Rectal cancer; Colon cancer; Colorectal; Microsatellite instability; CpG island methylator phenotype; Survival. T he term colorectal cancer is frequently used to discuss both colon and rectal cancers as a common entity. Grouping these two anatomically distinct diseases is an oversimplification clinically and biologically. Just as distinctions have been drawn between right-sided and left-sided colon cancers, 1,2 colon cancers differ from rectal cancers. 3Y5 Clinically, surgeons and medical oncologists distinguish colon from rectal adenocarcinoma because location determines operative and adjuvant treatment decisions. Beyond the anatomic distinction, underlying biology likely contributes to oncogenesis and outcomes. 6 Colorectal cancer is known to arise from normal mu- cosa via at least three oncogenic pathways. Chromosomal instability, or the classical adenoma-to-carcinoma sequence as described by Vogelstein, is characterized by accumu- lation of mutations in tumor suppressor genes and onco- genes such as KRAS that control cell growth and death. 7 Loss of the DNA mismatch repair function provides a second mechanism for cancer development, resulting in microsatellite unstable (microsatellite instability high (MSI-H)) cancers. 8 MSI-H tumors may occur via germline defects in mismatch repair genes, as in Lynch syndrome, 9,10 or more commonly via somatic failure of the mismatch repair system by epigenetic silencing of the MLH1 gene DISEASES OF THE COLON &RECTUM VOLUME 52: 6 (2009) 1039 Dr. Church has received honorariums from Myriad Genetics and Salix; he is a salaried employee of the Cleveland Clinic/Cologene. Read at the meeting of The American Society of Colon and Rectal Surgeons, Boston, Massachusetts, June 7 to 11, 2008 Address of correspondence: Matthew F. Kalady, M.D., 9500 Euclid Avenue, A30, Cleveland, Ohio 44195. E-mail: kaladym@ccf.org Dis Colon Rectum 2009; 52: 1039Y1045 DOI: 10.1007/DCR.0b013e31819edbd4 BThe ASCRS 2009 Copyright @ The ASCRS 2009. Unauthorized reproduction of this article is prohibited.