title: Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions.
abstract: Colon cancer is a clinically diverse disease. This heterogeneity makes it difficult to determine which patients will benefit most from adjuvant therapy and impedes the development of new targeted agents. More insight into the biological diversity of colon cancers, especially in relation to clinical features, is therefore needed. We demonstrate, using an unsupervised classification strategy involving over 1,100 individuals with colon cancer, that three main molecularly distinct subtypes can be recognized. Two subtypes have been previously identified and are well characterized (chromosomal-instable and microsatellite-instable cancers). The third subtype is largely microsatellite stable and contains relatively more CpG island methylator phenotype-positive carcinomas but cannot be identified on the basis of characteristic mutations. We provide evidence that this subtype relates to sessile-serrated adenomas, which show highly similar gene expression profiles, including upregulation of genes involved in matrix remodeling and epithelial-mesenchymal transition. The identification of this subtype is crucial, as it has a very unfavorable prognosis and, moreover, is refractory to epidermal growth factor receptor-targeted therapy.
authors.affiliation: Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center (AMC), Amsterdam, The Netherlands.
authors.forename: Felipe
authors.initials: F
authors.lastname: De Sousa E Melo
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Marnix
authors.initials: M
authors.lastname: Jansen
authors.forename: Evelyn
authors.initials: E
authors.lastname: Fessler
authors.forename: Anne
authors.initials: A
authors.lastname: Trinh
authors.forename: Laura P M H
authors.initials: LP
authors.lastname: de Rooij
authors.forename: Joan H
authors.initials: JH
authors.lastname: de Jong
authors.forename: Onno J
authors.initials: OJ
authors.lastname: de Boer
authors.forename: Ronald
authors.initials: R
authors.lastname: van Leersum
authors.forename: Maarten F
authors.initials: MF
authors.lastname: Bijlsma
authors.forename: Hans
authors.initials: H
authors.lastname: Rodermond
authors.forename: Maartje
authors.initials: M
authors.lastname: van der Heijden
authors.forename: Carel J M
authors.initials: CJ
authors.lastname: van Noesel
authors.forename: Jurriaan B
authors.initials: JB
authors.lastname: Tuynman
authors.forename: Evelien
authors.initials: E
authors.lastname: Dekker
authors.forename: Florian
authors.initials: F
authors.lastname: Markowetz
authors.forename: Jan Paul
authors.initials: JP
authors.lastname: Medema
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000145:classification* / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis