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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.

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


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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