Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study

Sean P. Cleary, Michelle Cotterchio, Mark A. Jenkins, Hyeja Kim, Robert Bristow, Roger Green, Robert Haile, John L. Hopper, Loic LeMarchand, Noralane Lindor, Patrick Parfrey, John Potter, Ban Younghusband, Steven Gallinger

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Abstract

Background & Aims: The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene. Methods: A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification. Results: Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5-132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P = .01), had a higher proportion of right-sided (P = .01), synchronous cancers (P < .01), and personal history of adenomatous polyps (P = .003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02-2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P = .02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction < .001). Conclusions: Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.

Original languageEnglish (US)
Pages (from-to)1251-1260
Number of pages10
JournalGastroenterology
Volume136
Issue number4
DOIs
StatePublished - Apr 2009

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Cleary, S. P., Cotterchio, M., Jenkins, M. A., Kim, H., Bristow, R., Green, R., Haile, R., Hopper, J. L., LeMarchand, L., Lindor, N., Parfrey, P., Potter, J., Younghusband, B., & Gallinger, S. (2009). Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study. Gastroenterology, 136(4), 1251-1260. https://doi.org/10.1053/j.gastro.2008.12.050