ColoType: a forty gene signature for consensus molecular subtyping of colorectal cancer tumors using whole-genome assay or targeted RNA-sequencing

Steven A Buechler; Melissa T Stephens; Amanda B Hummon; Katelyn Ludwig; Emily Cannon; Tonia C Carter; Jeffrey Resnick; Yesim Gökmen-Polar; Sunil S Badve

doi:10.1038/s41598-020-69083-y

ColoType: a forty gene signature for consensus molecular subtyping of colorectal cancer tumors using whole-genome assay or targeted RNA-sequencing

Sci Rep. 2020 Jul 21;10(1):12123. doi: 10.1038/s41598-020-69083-y.

Authors

Steven A Buechler¹, Melissa T Stephens², Amanda B Hummon³, Katelyn Ludwig⁴, Emily Cannon⁵, Tonia C Carter⁶, Jeffrey Resnick⁷, Yesim Gökmen-Polar⁸, Sunil S Badve^{8

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Affiliations

¹ Department of Applied and Computational Mathematics and Statistics, Harper Cancer Research Institute, University of Notre Dame, 102B Crowley Hall, Notre Dame, IN, 46556, USA. steve@nd.edu.
² Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, IN, USA.
³ Department of Chemistry and Biochemistry, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
⁴ Functional Genetics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁵ Department of Applied and Computational Mathematics and Statistics, Harper Cancer Research Institute, University of Notre Dame, 102B Crowley Hall, Notre Dame, IN, 46556, USA.
⁶ Center for Precision Medicine Research, Marshfield Clinic, Marshfield, WI, USA.
⁷ Department of Pathology, Marshfield Clinic, Marshfield, WI, USA.
⁸ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN, USA.

Abstract

Colorectal cancer (CRC) tumors can be partitioned into four biologically distinct consensus molecular subtypes (CMS1-4) using gene expression. Evidence is accumulating that tumors in different subtypes are likely to respond differently to treatments. However, to date, there is no clinical diagnostic test for CMS subtyping. In this study, we used novel methodology in a multi-cohort training domain (n = 1,214) to develop the ColoType scores and classifier to predict CMS1-4 based on expression of 40 genes. In three validation cohorts (n = 1,744, in total) representing three distinct gene-expression measurement technologies, ColoType predicted gold-standard CMS subtypes with accuracies 0.90, 0.91, 0.88, respectively. To accommodate for potential intratumoral heterogeneity and tumors of mixed subtypes, ColoType was designed to report continuous scores measuring the prevalence of each of CMS1-4 in a tumor, in addition to specifying the most prevalent subtype. For analysis of clinical specimens, ColoType was also implemented with targeted RNA-sequencing (Illumina AmpliSeq). In a series of formalin-fixed, paraffin-embedded CRC samples (n = 49), ColoType by targeted RNA-sequencing agreed with subtypes predicted by two independent methods with accuracies 0.92, 0.82, respectively. With further validation, ColoType by targeted RNA-sequencing, may enable clinical application of CMS subtyping with widely-available and cost-effective technology.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Algorithms
Colorectal Neoplasms / classification*
Colorectal Neoplasms / genetics
Consensus
Exome Sequencing
Female
Gene Expression Profiling / methods*
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks*
Humans
Male
Sequence Analysis, RNA