Originally published as JCO Early Release 10.1200/JCO.2008.21.6853 on July 20 2009

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Google Scholar Articles by Lubbe, S. J. Articles by Houlston, R. S. PubMed PubMed Citation Articles by Lubbe, S. J. Articles by Houlston, R. S. Social Bookmarking                            What's this?

Clinical Implications of the Colorectal Cancer Risk Associated With MUTYH Mutation

From the Section of Cancer Genetics, Institute of Cancer Research, Sutton, SM2 5NG, United Kingdom.

Corresponding author: Richard S. Houlston, MD, Institute of Cancer Research, 15 Cotswold Rd, Sutton, Surrey, United Kingdom SM2 5NG; e-mail: Richard.Houlston{at}icr.ac.uk.

Purpose Biallelic mutations in the base excision DNA repair gene MUTYH predispose to colorectal cancer (CRC). Evidence that monoallelic mutations also confer an elevated CRC risk is controversial. Precise quantification of the CRC risk and the phenotype associated with MUTYH mutations is relevant to the counseling, surveillance, and clinical management of at-risk individuals.

Methods We analyzed a population-based series of 9,268 patients with CRC and 5,064 controls for the Y179C and G396D MUTYH mutations. We related genotypes to phenotype and calculated genotype-specific CRC risks.

Results Overall, biallelic mutation status conferred a 28-fold increase in CRC risk (95% CI,17.66 to 44.06); this accounted for 0.3% of CRCs in the cohort. Genotype relative risks of CRC were strongly age dependent, but penetrance was incomplete at age 60 years. CRC that developed in the context of biallelic mutations were microsatellite stable. Biallelic mutation carriers were more likely to have proximal CRC (P = 4.0 x 10^–4) and synchronous polyps (P = 5.7 x 10^–9) than noncarriers. The performance characteristics of clinicopathologic criteria for the identification of biallelic mutations are poor. Monoallelic mutation was not associated with an increased CRC risk (odds ratio, 1.07; 95% CI, 0.87 to 1.31).

Conclusion The high risk and the propensity for proximal disease associated with biallielic MUTYH mutation justify colonoscopic surveillance. Although mutation screening should be directed to patients with APC-negative polyposis and early-onset proximal MSS CRC in whom detection rates will be highest, the expanded phenotype associated with MUTYH mutation needs to be recognized. There is no evidence than monoallelic mutation status per se is clinically important.

Supported by Cancer Research UK, CORE, the National Cancer Research Network and the European Union (CCPRB); by Grant No. QLG2-CT-2001-01861 from the Cancer Research UK, CORE, and the European Commission; by Cancer Research UK (PhD studentship, S.L.); by NCRN; and by NHS funding to the NIHR Biomedical Research Centre.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?