Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer

Abstract

Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first-and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56–2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18–4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07–12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18–5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5–8%) for men and 4% (95%CI 3–6%) for women; for gastric cancer, 2% (95%CI 1–3%) for men and 0.7% (95%CI 0.5–1%) for women; for liver cancer, 1% (95%CI 0.3–3%) for men and 0.3% (95%CI 0.1–1%) for women and for endometrial cancer, 4% (95%CI 2–8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.

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

“…Individuals with a germline mutation in one allele of the MUTYH gene are thought to have a modest or slightly increased risk of CRC. [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.…”

Risk Prediction Models for Colorectal Cancer: A Review

“…Increased risks of various extracolonic cancers have been reported: cancers of the uterus, stomach, ovary, ureter, renal pelvis, brain, small bowel, and hepatobiliary tract in Lynch syndrome (101); cancers of the brain, thyroid, and liver in familial adenomatous polyposis (102); and cancers of the uterus and stomach in monoallelic MUTYH mutation carriers (103), and cancers of the duodenum, bladder, skin, and ovary in biallelic MUTYH mutation carriers (104). Even within families not known to be segregating a high-risk mutation, CRC risk is higher for those with a family history of extracolonic cancers (105)(106)(107).…”

MutYH mutation carriers have increased breast cancer risk

“…7 It is known that mutations in mismatch-repair genes increase susceptibility to cancer in organs other than the colon, but former data published regarding a possible association between MutYH mutations and breast cancer risk are conflicting. [8][9][10][11][12][13][14] We studied the prevalence of the 2 commonly described founder mutations in MutYH, a glycine-to-aspartic acid substitution at codon 396 (G396D) and a tyrosine-to-cysteine substitution at codon 179 (Y179C), in a case-control study of breast cancer that was restricted to Sephardi Jews in whom we noted a high prevalence of these mutations (unpublished results).…”