Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Progress
  • Published:

New insights into the aetiology of colorectal cancer from genome-wide association studies

Abstract

Genome-wide association studies have recently identified ten common genetic variants associated with colorectal cancer susceptibility, several suggesting the involvement of components of the transforming growth factor beta (TGFβ) superfamily signalling pathway. To date, no causal sequence variants have been identified, and risk seems to be mediated through effects on gene regulation. Several markers are located close to poorly characterized genes or in gene deserts, raising challenges for elucidating mechanisms of susceptibility. Disease-associated common genetic variation offers the potential to refine risk stratification within populations and enable more targeted disease prevention strategies.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The TGFβ signalling pathway and its role in colorectal cancer.

Similar content being viewed by others

References

  1. World Health Organization.World Cancer Report (eds Stewart B. W. & Kleihues P.) 13 (IARC, Lyon, 2003).

  2. Barnetson, R. A. et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N. Engl. J. Med. 354, 2751–2763 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Towler, B. P., Irwig, L., Glasziou, P., Weller, D. & Kewenter, J. Screening for colorectal cancer using the faecal occult blood test, hemoccult. Cochrane Database Syst. Rev. 2007, CD001216 (2000).

    Google Scholar 

  4. Jarvinen, H. J. et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 118, 829–834 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Bost, B., de Vienne, D., Hospital, F., Moreau, L. & Dillmann, C. Genetic and nongenetic bases for the L-shaped distribution of quantitative trait loci effects. Genetics 157, 1773–1787 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Mackay, T. F. C. The genetic architecture of quantitative traits. Annu. Rev. Genet. 35, 303–339 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Foulkes, W. D. Inherited susceptibility to common cancers. N. Engl. J. Med. 359, 2143–2153 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer — analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. 343, 78–85 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Yingling, J. M., Blanchard, K. L. & Sawyer, J. S. Development of TGF-β signalling inhibitors for cancer therapy. Nature Rev. Drug Discov. 3, 1011–1022 (2004).

    Article  CAS  Google Scholar 

  10. The International HapMap Consortium.The International HapMap Project. Nature 426, 789–796 (2003).

  11. Kruglyak, L. The road to genome-wide association studies. Nature Rev. Genet. 9, 314–318 (2008).

    Article  CAS  PubMed  Google Scholar 

  12. McCarthy, M. I. et al. Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Rev. Genet. 9, 356–369 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Tenesa, A. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nature Genet. 40, 631–637 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Antoniou, A. C. & Easton, D. F. Polygenic inheritance of breast cancer: implications for design of association studies. Genet. Epidemiol. 25, 190–202 (2003).

    Article  PubMed  Google Scholar 

  15. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nature Genet. 39, 984–988 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Zanke, B. W. et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nature Genet. 39, 989–994 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Broderick, P. et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nature Genet. 39, 1315–1317 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Jaeger, E. et al. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nature Genet. 40, 26–28 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Tomlinson, I. P. et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nature Genet. 40, 623–630 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Houlston, R. S. et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nature Genet. 40, 1426–1435 (2008).

    Article  CAS  PubMed  Google Scholar 

  21. Howe, J. R. et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J. Med. Genet. 41, 484–491 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Valle, L. et al. Germline allele-specific expression of TGFBR1 confers an increased risk of colorectal cancer. Science 321, 1361–1365 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Blobe, G. C., Schiemann, W. P. & Lodish, H. F. Role of transforming growth factor beta in human disease. N. Engl. J. Med. 342, 1350–1358 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Guilford, P. et al. E-cadherin germline mutations in familial gastric cancer. Nature 392, 402–405 (1998).

    Article  CAS  PubMed  Google Scholar 

  25. Okamoto, H., Yasui, K., Zhao, C., Arii, S. & Inazawa, J. PTK2 and EIF3S3 genes may be amplification targets at 8q23-q24 and are associated with large hepatocellular carcinomas. Hepatology 38, 1242–1249 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Savinainen, K. J. et al. Expression and copy number analysis of TRPS1, EIF3S3 and MYC genes in breast and prostate cancer. Br. J. Cancer 90, 1041–1046 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shima, H. et al. Loss of heterozygosity on chromosome 10p14-p15 in colorectal carcinoma. Pathobiology 72, 220–224 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Haiman, C. A. et al. A common genetic risk factor for colorectal and prostate cancer. Nature Genet. 39, 954–956 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Ghoussaini, M. et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl Cancer Inst. 100, 962–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Falconer, D. S. & Mackay, T. F. C. Introduction to Quantitative Genetics (Longman, 1996).

    Google Scholar 

  31. Wray, N. R., Goddard, M. E. & Visscher, P. M. Prediction of individual genetic risk to disease from genome-wide association studies. Genome Res. 17, 1520–1528 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang, E. T. et al. Alternative isoform regulation in human tissue transcriptomes. Nature 456, 470–476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bodmer, W. & Bonilla, C. Common and rare variants in multifactorial susceptibility to common diseases. Nature Genet. 40, 695–701 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Derynck, R. & Zhang, Y. E. Smad-dependent and Smad-independent pathways in TGF-β family signalling. Nature 425, 577–584 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Peck, J. W., Oberst, M., Bouker, K. B., Bowden, E. & Burbelo, P. D. The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization. J. Biol. Chem. 277, 43924–43932 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Chang, Y. W., Marlin, J. W., Chance, T. W. & Jakobi, R. RhoA mediates cyclooxygenase-2 signaling to disrupt the formation of adherens junctions and increase cellmotility. Cancer Res. 66, 11700–11708 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Howe, J. R. et al. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science 280, 1086–1088 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Huang, S. C. et al. Genetic heterogeneity in familial juvenile polyposis. Cancer Res. 60, 6882–6885 (2000).

    CAS  PubMed  Google Scholar 

  39. Woodford-Richens, K. L. et al. SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway. Proc. Natl Acad. Sci. USA 98, 9719–9723 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kodach, L. L. et al. The bone morphogenetic protein pathway is inactivated in the majority of sporadic colorectal cancers. Gastroenterology 134, 1332–1341 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Parsons, R. et al. Microsatellite instability and mutations of the transforming growth factor β type II receptor gene in colorectal cancer. Cancer Res. 55, 5548–5550 (1995).

    CAS  PubMed  Google Scholar 

  42. Pasche, B. et al. Somatic acquisition and signaling of TGFBR1*6A in cancer. JAMA 294, 1634–1646 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Visscher, P. M., Hill, W. G. & Wray, N. R. Heritability in the genomics era — concepts and misconceptions. Nature Rev. Genet. 9, 255–266 (2008).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work that forms the basis of this discussion is supported by Cancer Research UK (C348/A8896, C48/A6361), and the Scottish Executive Chief Scientist's Office (CZB/4/449) — a centre grant from CORE as part of the Digestive Cancer Campaign. We acknowledge those in the Colon Cancer Genetics Group who have contributed to the work reviewed, particularly S. Farrington and H. Campbell, as well as our collaborators R. Houlston and I. Tomlinson and their groups. We thank R. Wilson and N. Cartwright, all of who worked on the COGS and SOCCS administrative teams, R. Cetnarskyj and the research nurse teams who recruited in Scotland, and all clinicians throughout Scotland at collaborating centres. We acknowledge N. Wray and P. Visscher for comments on BOX 1 and for sharing unpublished data on prediction models of genetic risk.

Author information

Authors and Affiliations

Authors

Related links

Related links

FURTHER INFORMATION

Malcolm G. Dunlop's homepage

Glossary

Excess familial risk

The increased risk of developing the disease in a relative of an affected individual. It is usually, and more appropriately, referred to for a specific type of relative. For example, the full-sibling relative risk (s) is the increased risk of developing a disease for a full sibling of an affected person compared with the risk of a person from the general population.

Heritability

The proportion of phenotypic variance that is explained by inherited genetic factors.

Liability scale

The assumed and unobserved normally distributed risk scale. In the case of a disease, those individuals with a liability score above a specific threshold will have the disease.

Observed scale

For a disease trait, the observed scale of the phenotype is either disease or non-disease. The heritability in the observed scale depends on the disease prevalence.

Odds ratio

A measure of the effect size. It is the odds of exposure (that is, a specific allele) among the cases divided by the odds of exposure among the controls. In casecontrol studies, the odds ratio is used as an approximation to the relative risk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tenesa, A., Dunlop, M. New insights into the aetiology of colorectal cancer from genome-wide association studies. Nat Rev Genet 10, 353–358 (2009). https://doi.org/10.1038/nrg2574

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg2574

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing