Comparative molecular analyses of left-sided colon, right-sided colon, and rectal cancers

// Mohamed E. Salem 1, * , Benjamin A. Weinberg 1, * , Joanne Xiu 2 , Wafik S. El-Deiry 3 , Jimmy J. Hwang 4 , Zoran Gatalica 2 , Philip A. Philip 5 , Anthony F. Shields 5 , Heinz-Josef Lenz 6 and John L. Marshall 1 1 Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA 2 Caris Life Sciences, Phoenix, AZ, USA 3 Fox Chase Cancer Center, Philadelphia, PA, USA 4 Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA 5 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA 6 Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA * Co-first authors Correspondence to: Mohamed E. Salem, email: mohamed.e.salem@gunet.georgetown.edu Keywords: colorectal neoplasms, colonic neoplasms, rectal neoplasms, DNA mutational analysis, immunohistochemistry Received: June 01, 2017     Accepted: August 15, 2017     Published: September 21, 2017 ABSTRACT Tumor sidedness has emerged as an important prognostic and predictive factor in the treatment of colorectal cancer. Recent studies demonstrate that patients with advanced right-sided colon cancers have a worse prognosis than those with left-sided colon or rectal cancers, and these patient subgroups respond differently to biological therapies. Historically, management of patients with metastatic colon and rectal cancers has been similar, and colon and rectal cancer patients have been grouped together in large clinical trials. Clearly, the differences in molecular biology among right-sided colon, left-sided colon, and rectal cancers should be further studied in order to account for disparities in clinical outcomes. We profiled 10,570 colorectal tumors (of which 2,413 were identified as arising from the left colon, right colon, or rectum) using next-generation sequencing, immunohistochemistry, chromogenic in-situ hybridization, and fragment analysis (Caris Life Sciences, Phoenix, AZ). Right-sided colon cancers had higher rates of microsatellite instability, more frequent aberrant activation of the EGFR pathway including higher BRAF and PIK3CA mutation rates, and increased mutational burden compared to left-sided colon and rectal cancers. Rectal cancers had higher rates of TOPO1 expression and Her2/neu amplification compared to both left- and right-sided colon cancers. Molecular variations among right-sided colon, left-sided colon, and rectal tumors may contribute to differences in clinical behavior. The site of tumor origin (left colon, right colon, or rectum) should certainly be considered when selecting treatment regimens and stratifying patients for future clinical trials.