Universität zu Köln

Fessler, E., Jansen, M., Melo, F. De Sousa E., Zhao, L., Prasetyanti, P. R., Rodermond, H., Kandimalla, R., Linnekamp, J. F., Franitza, M., van Hooff, S. R., de Jong, J. H., Oppeneer, S. C., van Noesel, C. J. M., Dekker, E., Stassi, G., Wang, X., Medema, J. P. and Vermeulen, L. (2016). A multidimensional network approach reveals microRNAs as determinants of the mesenchymal colorectal cancer subtype. Oncogene, 35 (46). S. 6026 - 6038. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fessler, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jansen, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Melo, F. De Sousa E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Prasetyanti, P. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rodermond, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kandimalla, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Linnekamp, J. F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Franitza, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Hooff, S. R. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Jong, J. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Oppeneer, S. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Noesel, C. J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dekker, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Stassi, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wang, X. UNSPECIFIED UNSPECIFIED UNSPECIFIED Medema, J. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeulen, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-255607
DOI:	10.1038/onc.2016.134
Journal or Publication Title:	Oncogene
Volume:	35
Number:	46
Page Range:	S. 6026 - 6038
Date:	2016
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MIR-200 FAMILY; ANALYSES IDENTIFY; POOR SURVIVAL; EXPRESSION; TRANSITION; METASTASIS; ZEB1; EMT; HETEROGENEITY; PHENOTYPE Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25560