Originally published as JCO Early Release 10.1200/JCO.2008.20.3364 on March 23 2009

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Implications of Familial Colorectal Cancer Risk Profiles and Microsatellite Instability Status

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

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

Purpose Estimating familial colorectal cancer (CRC) risk is clinically important in being able to discriminate between high- and low-risk groups. To quantify familial CRC risks associated with mismatch repair (MMR) deficient and microsatellite stable (MSS) tumors, we analyzed 2,941 population-based cases of CRC.

Patients and Methods MMR status in CRCs was established by testing for microsatellite instability (MSI). MUTYH status was assigned by screening for Y165C and G382D variants. Age-specific relative and absolute CRC risks in first-degree relatives (FDRs) were calculated, and the most likely genetic models of familial aggregation were derived.

Results CRC risks in FDRs were strongly associated with MSI status (MSI, standardized incidence ratio [SIR] = 4.28, 95% CI, 3.51 to 5.17; MSS, SIR = 1.91, 95% CI, 1.73 to 2.11), early-onset disease (MSI patient age < 55 years, SIR = 10.96, 95% CI, 8.32 to 14.17; MSS patient age < 55 years, SIR = 2.3, 95% CI, 1.88 to 2.85), and having more than one affected FDR (MSI, SIR = 10.00, 95% CI, 7.74 to 12.72; MSS, SIR = 2.78, 95% CI, 2.18 to 3.48). The familial aggregation of CRC associated with MSI cancer was parsimonious with dominant model conferring a high CRC risk at early ages. Approximately 69% of the excess familial risk in FDRs can be ascribed to MSS CRC, and although the pattern of familial risk supports recessive susceptibility in addition to MUTYH, the absolute risk of CRC is at best modest.

Conclusion The results from this analysis should enable an individual's risk of CRC to be more accurately estimated, thus maximizing the value of screening programs. Results also have utility in the design of genetic analyses to identify novel disease alleles.

Supported by the National Cancer Research Network. Grant support was provided by Cancer Research UK, CORE, and the European Commission (Grant No. QLG2-CT-2001-01861). S.J.L. is in receipt of a PhD studentship from Cancer Research UK. I.P.C. was in receipt of a Clinical Training Fellowship from St George's Hospital, London, United Kingdom.

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

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				S. J. Lubbe, M. C. Di Bernardo, I. P. Chandler, and R. S. Houlston Clinical Implications of the Colorectal Cancer Risk Associated With MUTYH Mutation J. Clin. Oncol., August 20, 2009; 27(24): 3975 - 3980. [Abstract] [Full Text] [PDF]