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. 2018 Mar 1;24(5):1062-1072.
doi: 10.1158/1078-0432.CCR-17-2484. Epub 2017 Nov 27.

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

Jonathan M Loree  1 , Allan A L Pereira  1 , Michael Lam  1 , Alexandra N Willauer  1 , Kanwal Raghav  1 , Arvind Dasari  1 , Van K Morris  1 , Shailesh Advani  1 , David G Menter  1 , Cathy Eng  1 , Kenna Shaw  2 , Russell Broaddus  3 , Mark J Routbort  4 , Yusha Liu  5 , Jeffrey S Morris  5 , Rajyalakshmi Luthra  4 , Funda Meric-Bernstam  6 , Michael J Overman  1 , Dipen Maru  3 , Scott Kopetz  7
Affiliations

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

Jonathan M Loree et al. Clin Cancer Res. .

Abstract

Purpose: 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.Experimental Design: 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.Results: Mutation prevalence differed by side and location for TP53, KRAS, BRAFV600, PIK3CA, SMAD4, CTNNB1, GNAS, and PTEN Within left- and right-sided tumors, there remained substantial variations in mutation rates. For example, within right-sided tumors, RAS mutations decreased from 70% for cecal, to 43% for hepatic flexure location (P = 0.0001), while BRAFV600 mutations increased from 10% to 22% between the same locations (P < 0.0001). Within left-sided tumors, the sigmoid and rectal region had more TP53 mutations (P = 0.027), less PIK3CA (P = 0.0009), BRAF (P = 0.0033), or CTNNB1 mutations (P < 0.0001), and less MSI (P < 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.Conclusions: 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. Clin Cancer Res; 24(5); 1062-72. ©2017 AACRSee related commentary by Dienstmann, p. 989.

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Conflict of interest statement

Disclosures: All authors report no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Relative prevalence of key oncogenic alterations at specific primary tumor locations in patients with metastatic colorectal cancer.
Figure 2
Figure 2
K-mode clustering of mutational profiles of metastatic colorectal cancers classified by tumor location to help establish an optimal right vs left cut point. Each cluster represents a distinct group of mutations that either commonly co-occur or are mutually exclusive and are used for grouping similar patients together.
Figure 3
Figure 3
Relative prevalence of Consensus Molecular Subtypes at specific primary tumor locations. Sub-caption: MSI-H= microsatellite instability high.
Figure 4
Figure 4
Comparison of overall survival based on primary tumor location in (A) a univariate model assessing only tumor location and (B) a multivariate proportional hazards model controlling for co-variates that differed based on tumor location. Sub-caption: Variables within the cartoon represent the hazard ratio for individual locations followed by the 95% confidence interval within square brackets.
See this image and copyright information in PMC

Comment in

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