title: A multidimensional network approach reveals microRNAs as determinants of the mesenchymal colorectal cancer subtype.
abstract: Colorectal cancer (CRC) is a heterogeneous disease posing a challenge for accurate classification and treatment of this malignancy. There is no common genetic molecular feature that would allow for the identification of patients at risk for developing recurrences and thus selecting patients who would benefit from more stringent therapies still poses a major clinical challenge. Recently, an international multicenter consortium (CRC Subtyping Consortium) was established aiming at the classification of CRC patients in biologically homogeneous CRC subtypes. Four consensus molecular subtypes (CMSs) were identified, of which the mesenchymal CMS4 presented with worse prognosis signifying the importance of identifying these patients. Despite the large number of samples analyzed and their clear association with unifying biological programs and clinical features, single-driver mutations could not be identified and patients are heterogeneous with regard to currently used clinical markers. We therefore set out to define the regulatory mechanisms underlying the distinct gene expression profiles using a network-based approach involving multiple molecular modalities such as gene expression, methylation levels and microRNA (miR) expression. The miR-200 family presented as the most powerful determinant of CMS4-specific gene expression, tuning the majority of genes differentially expressed in the poor prognosis subtype, including genes associated with the epithelial-mesenchymal transition program. Furthermore, our data show that two epigenetic marks, namely the methylation of the two miR-200 promoter regions, can identify tumors belonging to the mesenchymal subtype and is predictive of disease-free survival in CRC patients. Importantly, epigenetic silencing of the miR-200 family is also detected in epithelial CRC cell lines that belong to the mesenchymal CMS. We thus show that determining regulatory networks is a powerful strategy to define drivers of distinct cancer subtypes, which possess the ability to identify subtype affiliation and to shed light on biological behavior.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Fessler
authors.affiliation: Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: De Sousa E Melo
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
authors.forename: L
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: P R
authors.initials: PR
authors.lastname: Prasetyanti
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Rodermond
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Kandimalla
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Linnekamp
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Franitza
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: S R
authors.initials: SR
authors.lastname: van Hooff
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: J H
authors.initials: JH
authors.lastname: de Jong
authors.affiliation: Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Oppeneer
authors.affiliation: Department of Pathology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: C J M
authors.initials: CJ
authors.lastname: van Noesel
authors.affiliation: Department of Gastroenterology, AMC, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Dekker
authors.affiliation: Cellular and Molecular Pathophysiology Laboratory, Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stassi
authors.affiliation: Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, Hong Kong.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.|Cancer Genomics Center, Utrecht, The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: L
authors.identifier: 0000-0002-6066-789X
authors.initials: L
authors.lastname: Vermeulen
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D019295:Computational Biology / Q000379:methods; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic; D059467:Transcriptome
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs