Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study

Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, Haile R, Hopper JL, 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 136:1251-1260

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=""><.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="">