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Evaluation of germline BMP4 mutation as a cause of colorectal cancer†

  1. Steven J. Lubbe1,
  2. Alan M. Pittman1,
  3. Cornelis Matijssen2,
  4. Philip Twiss1,
  5. Bianca Olver1,
  6. Amy Lloyd1,
  7. Mobshra Qureshi1,
  8. Nathan Brown2,
  9. Emma Nye3,
  10. Gordon Stamp3,4,
  11. Julian Blagg2,
  12. Richard S. Houlston1,*

Article first published online: 14 OCT 2010

DOI: 10.1002/humu.21376

Issue

Human Mutation

Human Mutation

Volume 32, Issue 1, pages E1928–E1938, January 2011

Additional Information

How to Cite

Lubbe, S. J., Pittman, A. M., Matijssen, C., Twiss, P., Olver, B., Lloyd, A., Qureshi, M., Brown, N., Nye, E., Stamp, G., Blagg, J. and Houlston, R. S. (2011), Evaluation of germline BMP4 mutation as a cause of colorectal cancer. Human Mutation, 32: E1928–E1938. doi: 10.1002/humu.21376

Author Information

  1. 1

    Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, UK

  2. 2

    Medicinal Chemistry, Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton SM2 5NG, UK

  3. 3

    Experimental Pathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln/s Inn Fields, London WC2A 3PX, UK

  4. 4

    Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK; and Imperial College Faculty of Medicine, Imperial College Hammersmith Campus, Du Cane Road, London W12 ONN, UK

*Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey. SM2 5NG, Fax: +44 (0) 208 722 4365

  1. †

    Communicated by Riccardo Fodde

Publication History

  1. Issue published online: 22 DEC 2010
  2. Article first published online: 14 OCT 2010
  3. Manuscript Accepted: 7 SEP 2010
  4. Manuscript Received: 13 MAY 2010

Funded by

  • Cancer Research UK (CRUK), and the European Union (EU). Grant Number: C1298/A8362
  • Bobby Moore Fund. Grant Number: C309/A827
  • Cancer Research UK Centre for Cancer Therapeutics (CRUK)CPRB. Grant Number: LSHC-CT-2004-503465 (EU)

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Keywords:

  • bone morphogenetic protein-4;
  • BMP4;
  • rare mutations;
  • colorectal cancer

Abstract

Transforming growth factor-â (TGF-â) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-â family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localizes to the N-terminal of the TGF-â1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants. © 2010 Wiley-Liss, Inc.

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