Selective Analysis of Cancer-cell Intrinsic Transcriptional Traits Defines Novel Clinically Relevant Subtypes of Colorectal Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2017 Jun 1

PMID 28561063

Citations 162

Authors

Claudio Isella

Francesco Brundu

Sara E Bellomo

Francesco Galimi

Eugenia Zanella

Roberta Porporato

Consalvo Petti

Alessandro Fiori

Francesca Orzan

Rebecca Senetta

Carla Boccaccio

Elisa Ficarra

Luigi Marchionni

Livio Trusolino

Enzo Medico

Andrea Bertotti

Affiliations

Soon will be listed here.

Abstract

Stromal content heavily impacts the transcriptional classification of colorectal cancer (CRC), with clinical and biological implications. Lineage-dependent stromal transcriptional components could therefore dominate over more subtle expression traits inherent to cancer cells. Since in patient-derived xenografts (PDXs) stromal cells of the human tumour are substituted by murine counterparts, here we deploy human-specific expression profiling of CRC PDXs to assess cancer-cell intrinsic transcriptional features. Through this approach, we identify five CRC intrinsic subtypes (CRIS) endowed with distinctive molecular, functional and phenotypic peculiarities: (i) CRIS-A: mucinous, glycolytic, enriched for microsatellite instability or KRAS mutations; (ii) CRIS-B: TGF-β pathway activity, epithelial-mesenchymal transition, poor prognosis; (iii) CRIS-C: elevated EGFR signalling, sensitivity to EGFR inhibitors; (iv) CRIS-D: WNT activation, IGF2 gene overexpression and amplification; and (v) CRIS-E: Paneth cell-like phenotype, TP53 mutations. CRIS subtypes successfully categorize independent sets of primary and metastatic CRCs, with limited overlap on existing transcriptional classes and unprecedented predictive and prognostic performances.

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