Risk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer

Abstract

We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks, through 70 y of age, of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%–11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%–8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC, diagnosed by 50 y of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men and (95% CI, 8.6%–17.7%) and 10% for women (95% CI, 6.7%–14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.

Quantifying the Utility of Single Nucleotide Polymorphisms to Guide Colorectal Cancer Screening

“…Then if G i is a random variable giving the number of risk alleles at SNP i for a random person from the population, then G 1 , ., G m , ., are all independent random variables (by linkage equilibrium) and the log-odds ratio for a random person is X 1 + … + X m (by the assumed multiplicative model), where X i = G i log OR i and OR i is the per-allele odds ratio for SNP i . A formula of Antoniou et al [14], derived rigorously in Win et al [15], then becomes . This shows that the log FRR is the sum of independent components from the known and unknown colorectal cancer-associated SNPs.…”

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 3.2017

“…[38][39][40] A recent study suggests that the risks may be higher than previously estimated. 41 This study analyzed 2,332 individuals with monoallelic MUTYH mutations among 9,504 relatives of 264 CRC cases with a MUTYH mutation. The estimated CRC risks, up to 70 years of age, were 7.2% for male carriers of monoallelic MUTYH mutations (95% CI, 4.6%-11.3%) and 5.6% for female carriers (95% CI, 3.6%-8.8%), irrespective of family history.…”

Cancer Screening Recommendations and Clinical Management of Inherited Gastrointestinal Cancer Syndromes in Childhood

“…MUTYH encodes a DNA glycosylase involved in DNA oxidative damage repair, and associated polyps and tumors have a C:G>A:T transversion phenotype, which is relatively uncommon in sporadic colorectal cancer (36,41,42). Controversy remains regarding whether monoallelic carriers have an increased risk for colorectal cancer in adulthood (43). Germline monoallelic MUTYH mutations have been identified in children diagnosed with Ewing sarcoma, medulloblastoma, B-lineage acute lymphoblastic leukemia, and high-grade glioma (44,45), but their contribution to childhood cancer etiology has not been established.…”