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Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions

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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 agents1. 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)2. 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.

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Figure 1: Unsupervised classification identifies three molecular distinct subtypes.
Figure 2: CCS3 tumors have poor prognosis, underlie previous prognostic classifiers and can be identified using a tissue microarray.
Figure 3: CCS3 tumors are resistant to therapy.
Figure 4: Poor-prognosis CCS3 tumors develop via the serrated pathway and express high levels of genes involved in matrix remodeling and EMT.

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Gene Expression Omnibus

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Gene Expression Omnibus

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Acknowledgements

We wish to thank P. van Sluijs and R. Volckmann for assistance with deriving gene expression profiles, J. Lascorz for sharing his collection of prognostic signatures, S. Kozar for important comments on the manuscript, and K. Punt, I. Nagtegaal and P. Kuppen for valuable insights from their patient cohorts. This work was supported by a Vici grant from the Netherlands Organisation for Scientific Research to J.P.M. and Dutch Cancer Society grants (2009-4416 and 2012-5735). L.V. is supported by a Koningin Wilhelmina Fonds (KWF, Dutch Cancer Society Fellowship).

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F.D.S.E.M., M.J., E.F., A.T., L.P.M.H.d.R., J.H.d.J., O.J.d.B., R.v.L., M.F.B., H.R. and M.v.d.H. performed experiments; M.J., C.J.M.v.N., J.B.T. and E.D. provided tissue and pathological assistance; F.D.S.E.M., X.W., F.M., J.P.M. and L.V. analyzed the data; and J.P.M. and L.V. supervised the project and wrote the manuscript. All authors approved the content of the manuscript.

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Correspondence to Jan Paul Medema or Louis Vermeulen.

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De Sousa E Melo, F., Wang, X., Jansen, M. et al. Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions. Nat Med 19, 614–618 (2013). https://doi.org/10.1038/nm.3174

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