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Author Notes:

steve@nd.edu

S.A.B. developed the methodology, carried out the data analysis and was lead author of the manuscript. A.B.H., M.T.S., K.L. and E.C. extracted and analyzed mRNA, performed RNA-seq and interpreted sequencing data. T.C.C. and J.R. identified patient samples to be included in the Marshfield cohort, and confirmed diagnosis by pathology review. Y.G.P. and S.S.B. performed pathological analysis, and extracted mRNA. S.A.B., A.B.H., Y.G.P. and S.S.B. designed the project. All authors reviewed the manuscript.

We are grateful to staff at Marshfield Clinic’s Center for Clinical Epidemiology and Population Health, Histology Department, and Office of Research Computing and Analytics for assistance in obtaining clinical data and glass slides of tumor samples for the Marshfield cohort. We thank Brent Harker, Notre Dame Genomics & Bioinformatics Core Facility, for organizing, executing and establishing protocols for RNA-seq analysis of the Marshfield cohort samples.

The University of Notre Dame has filed a patent application for ColoType with SAB as inventor. SAB is a founder of Claris GenomiX, Inc which is has obtained a license for this technology. Other authors reported no competing interests.

Subjects:

Research Funding:

Research partially supported by a Grant from Indiana Clinical Translational Sciences Institute (Grant no. PDT 468).

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • II/III COLON-CANCER
  • INTRINSIC SUBTYPES
  • CLASSIFICATION
  • HETEROGENEITY
  • RESPONSES
  • MODELS

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

Journal Title:

SCIENTIFIC REPORTS

Volume:

Volume 10, Number 1

Publisher:

, Pages 12123-12123

Type of Work:

Article | Final Publisher PDF

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.

Copyright information:

© The Author(s) 2020

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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