TY - JOUR
T1 - Clinical implications of the colorectal cancer risk associated with MUTYH mutation
AU - Lubbe, Steven J.
AU - Di Bernardo, Maria Chiara
AU - Chandler, Ian P.
AU - Houlston, Richard S.
PY - 2009/8/20
Y1 - 2009/8/20
N2 - 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 genotypespecific 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.
AB - 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 genotypespecific 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.
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U2 - 10.1200/JCO.2008.21.6853
DO - 10.1200/JCO.2008.21.6853
M3 - Article
C2 - 19620482
AN - SCOPUS:69849112388
VL - 27
SP - 3975
EP - 3980
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
SN - 0732-183X
IS - 24
ER -