Abstract 823: Colorectal cancer heterogeneity from a gene expression perspective.
Authors: Budinska Eva , Janotova Andrea , Tejpar Sabine , Popovici Vlad , D'Ario Giovanni , Lapique Nicolas , Sikora Katarzyna Otylia , Di Narzo Antonio Fabio , Yan Pu , Hodgson John Graeme , Weinrich Scott , Bosman Fred , Roth Arnaud , Delorenzi Mauro 
Published: August 2014

In a robust and unsupervised analysis of 1113 stage II-III CRC gene expression profiles from PETACC3 and 4 public datasets we defined a set of five gene expression subtypes which were validated in an independent set of 720 samples. We tested these subtypes with common clinico-pathological features, copy number variations, mutations in key cancer associated genes - such as BRAF or KRAS - and prognosis, and found important associations. The gene set enrichment analysis of groups of genes with similar gene expression patterns and existing CRC signatures followed by the literature search of gene members identified a number of biological motifs underlying the CRC gene expression heterogeneity, such as EMT/stroma, immune, proliferation, Wnt signaling, 20q chromosome, markers of enterocytes, secretory cell markers or lipid synthesis. Based on these results we named the subtypes A: Surface crypt, B: Lower crypt, C: CIMP-H-like, D: Mesenchymal and E: Mixed. Subtype A, specific by expression of markers of differentiated colon crypt cells was enriched for KRAS mutant tumors (77%); WNT-high proliferative subtype B had a good prognosis and comprised mainly MSS (100%) and left (76%); subtype C had the worse prognosis in SAR and was enriched for BRAFm (29%), right (73%), MSI (60%) and mucinous (38%) tumors. Subtype D, with the worse prognosis in OS and RFS was characteristic by high expression of EMT/stroma genes and subtype E enriched for p53 mutations (73%).

We performed nuclear β-catenin immunoreactivity scoring of paraffin sections of 133 samples and found significant associations with the subtypes. The supervised histopathological assessment of the same set of paraffin sections resulted in an identification of subtype specific morphological patterns (serrated and papillary pattern in subtype A, complex tubular pattern in subtypes B and E, solid and mucinous in subtype C, desmoplastic reaction in D). Next, we concentrated our efforts on gene networks analysis in order to identify subtype specific gene-gene interactions. These results further refined between-subtype differences. The proposed CRC characterization provides a molecular basis to different morphological patterns in CRC and the identified molecular motifs allow subtypes to be further interrogated functionally in vitro for driving oncogenic events.

Citation Format: Eva Budinska, Andrea Janotova, Sabine Tejpar, Vlad Popovici, Giovanni D'Ario, Nicolas Lapique, Katarzyna Otylia Sikora, Antonio Fabio Di Narzo, Pu Yan, John Graeme Hodgson, Scott Weinrich, Fred Bosman, Arnaud Roth, Mauro Delorenzi. Colorectal cancer heterogeneity from a gene expression perspective. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 823. doi:10.1158/1538-7445.AM2013-823