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Nat Commun. 2017 May 31;8:15107. doi: 10.1038/ncomms15107.

Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer.

Author information

1
Department of Oncology, University of Torino School of Medicine, 10060 Candiolo Torino, Italy.
2
Candiolo Cancer Institute-FPO IRCCS, 10060 Candiolo Torino, Italy.
3
Department of Control and Computer Engineering, Torino School of Engineering, 10129 Torino, Italy.
4
Department of Medical Sciences, University of Torino School of Medicine, 10060 Candiolo Torino, Italy.
5
Department of Oncology, Johns Hopkins University, Baltimore, 21287 Maryland, USA.
6
National Institute of Biostructures and Biosystems, INBB, 00136 Rome, Italy.

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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