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

Nature Medicine volume 19, pages 614–618 (2013)Cite this article

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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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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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Author notes

  1. Felipe De Sousa E Melo, Xin Wang, Jan Paul Medema and Louis Vermeulen: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental Molecular Medicine, Academic Medical Center (AMC), Amsterdam, The Netherlands

    Felipe De Sousa E Melo, Evelyn Fessler, Laura P M H de Rooij, Joan H de Jong, Ronald van Leersum, Maarten F Bijlsma, Hans Rodermond, Maartje van der Heijden, Jan Paul Medema & Louis Vermeulen

  2. Computational Biology Research Group, Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    Xin Wang, Anne Trinh & Florian Markowetz

  3. Department of Pathology, AMC, Amsterdam, The Netherlands

    Marnix Jansen, Onno J de Boer & Carel J M van Noesel

  4. Laboratory for Intestinal Stem Cell Biology, Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, UK

    Maartje van der Heijden & Louis Vermeulen

  5. Department of Colorectal Surgery, Oxford University Hospitals, Headley Way, Oxford, UK

    Jurriaan B Tuynman

  6. Department of Gastroenterology, AMC, Amsterdam, The Netherlands

    Evelien Dekker

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  1. Felipe De Sousa E Melo
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Contributions

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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The authors declare no competing financial interests.

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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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