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

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d7251632e279">Purpose</h5> <p id="P1">Colorectal cancers (CRCs) 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. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d7251632e284">Experimental Design</h5> <p id="P2">In 1,876 patients with CRC 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. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d7251632e289">Results</h5> <p id="P3">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 (P=0.0001), while <i>BRAF</i>V600 mutations increased from 10% to 22% between the same locations (P&lt;0.0001). Within left sided tumors, the sigmoid and rectal region had more <i>TP53</i> mutations (P=0.027), less <i>PIK3CA</i> (P=0.0009), <i>BRAF</i> (P=0.0033), or <i>CTNNB1</i> mutations (P&lt;0.0001), and less MSI (P&lt;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. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d7251632e319">Conclusions</h5> <p id="P4">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. </p> </div>