Gastroenterology

Gastroenterology

Volume 136, Issue 4, April 2009, Pages 1251-1260
Gastroenterology

Clinical—Alimentary Tract
Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study

https://doi.org/10.1053/j.gastro.2008.12.050Get rights and content

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.

Section snippets

Methods

CRC patients and controls were recruited through the resources of the Colorectal Cancer Family Registry (C-CFR), a National Cancer Institute–supported consortium dedicated to the study of genetic and epidemiologic factors in CRC. Recruitment of cases and controls was undertaken at 6 international study sites and included the collection of family history, epidemiologic and pathologic data, and the collection of pathologic specimens and blood samples for genetic testing. Recruitment also included

Results

A total of 6769 subjects were genotyped for 9 MYH mutations. Interpretable MS results were obtained for 98%–99% of subjects for each mutation. A total of 132 subjects who did not have complete screening results for all 9 mutations and 24 cases with germline mutations in mismatch repair genes (MLH1, MSH2, and MSH6) were excluded from the analysis. Three hundred and fifty samples were submitted randomly for repeat MS testing and there was 100% concordance among duplicate genotyping results. The

Discussion

The mutYh, or MYH, gene is a member of the base-excision repair pathway involved in the detection and repair of oxidative DNA damage.30 Al-Tassan et al5 described 2 mutations in the MYH gene, Y165C and G382D, in a Welsh family with CRC and multiple adenomatous polyps. These 2 mutations appear to account for almost 90% of MYH mutations in Caucasian patients of Northern European ancestry. Additional mutations have been described in Caucasians13, 31, 32 and individuals of South Asian descent.7

The

Acknowledgments

The authors thank Ellen Shi for her assistance with the polytomous logistic regression.

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      MUTYH is a base excision repair gene located on chromosome 1p34.3-p32.1 and its mutation leads to somatic G > T transversions in multiple genes, including APC and K-ras [10]. It has been reported that MAP is responsible for less than 1% of all CRCs [11]. In a cohort of 405 patients with oligopolyposis 7% was diagnosed with MAP at molecular genetic testing [12].

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    Conflict of interest The authors disclose no conflicts.

    Funding This work was supported by the National Cancer Institute, National Institutes of Health under RFA #CA-95-011, the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), and through cooperative agreements with members of the Colon Cancer Family Registry (CFRs) and P.I.s, and the National Cancer Institute of Canada (grant #13304 to S.G.) The content of this article does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. M.E.C. is supported by an Interdisciplinary Health Research Team Scholarship through the Canadian Institutes of Health Research.

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