Classifying Colorectal Cancer by Tumor Location Rather than Sidedness Highlights a Continuum in Mutation Profiles and Consensus Molecular Subtypes

<b>Purpose:</b> Colorectal cancers are classified as right/left-sided based on whether they occur before/after the splenic flexure, with established differences in molecular subtypes and outcomes. However, it is unclear if this division is optimal and whether precise tumor location provides further information.<b>Experimental Design:</b> In 1,876 patients with colorectal cancer, we compared mutation prevalence and overall survival (OS) according to side and location. Consensus molecular subtype (CMS) was compared in a separate cohort of 608 patients.<b>Results:</b> Mutation prevalence differed by side and location for <i>TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS</i>, and <i>PTEN</i> Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, <i>RAS</i> mutations decreased from 70% for cecal, to 43% for hepatic flexure location (<i>P</i> = 0.0001), while <i>BRAF</i>V600 mutations increased from 10% to 22% between the same locations (<i>P</i> < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more <i>TP53</i> mutations (<i>P</i> = 0.027), less <i>PIK3CA</i> (<i>P</i> = 0.0009), <i>BRAF</i> (<i>P</i> = 0.0033), or <i>CTNNB1</i> mutations (<i>P</i> < 0.0001), and less MSI (<i>P</i> < 0.0001) than other left-sided locations. Despite this, a left/right division preceding the transverse colon maximized prognostic differences by side and transverse colon tumors had K-modes mutation clustering that appeared more left than right sided. CMS profiles showed a decline in CMS1 and CMS3 and rise in CMS2 prevalence moving distally.<b>Conclusions:</b> Current right/left classifications may not fully recapitulate regional variations in tumor biology. Specifically, the sigmoid-rectal region appears unique and the transverse colon is distinct from other right-sided locations. <i>Clin Cancer Res; 24(5); 1062-72. ©2017 AACR</i><i>See related commentary by Dienstmann, p. 989</i>.