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

Mohamed E Salem,John L Marshall,Joanne Xiu,Zoran Gatalica,Jimmy J Hwang,Benjamin A Weinberg,Wafik S El-Deiry,Philip A Philip,Anthony F Shields,Heinz-Josef Lenz

doi:10.18632/oncotarget.21169

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.

Highlights

The impact of tumor location on patient survival and response to therapies has been shown in large clinical trials; the underlying tumor biology explaining these differences has not been systematically explored
Biomarker comparisons were performed on the 1,730 primary tumors, including 1,424 tested with immunohistochemistry (IHC), 753 with next-generation sequencing (NGS) on the MiSeq platform, and 70 with NGS on the NextSeq platform
KRAS mutation rates were similar (37.3% vs. 34.4%; P > 0.05) [9]. These differences offer insight into the potential use of EGFR inhibitors due to the fact that only patients with RAS and BRAF wild-type tumors derive benefit [10, 11]

Summary

Introduction

The impact of tumor location on patient survival and response to therapies has been shown in large clinical trials; the underlying tumor biology explaining these differences has not been systematically explored. Cancers arising from the colon and rectum are often grouped together and generally categorized as colorectal cancer (CRC) despite their distinctly different clinical behaviors and management needs. The right colon has a different embryological origin and blood supply from the left colon and rectum. The differential distribution of the four classes in various anatomic regions suggests biological differences in right-sided colon, left-sided colon, and rectal tumors. We investigated the proteomic and genetic aberrations of a large cohort of clinical CRC samples to further delineate these molecular differences

Methods

Results

Conclusion