Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH

Abstract

Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier’s risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age, and histories of cancer from their 1,903 first- and 3,255 second-degree relatives, were analysed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals [CIs]) for biallelic MUTYH mutation carriers were: urinary bladder cancer, 19(3.7–97); and ovarian cancer, 17(2.4–115). The HRs (95%CI) for monoallelic MUTYH mutation carriers were: gastric cancer, 9.3(6.7–13); hepatobiliary cancer, 4.5(2.7–7.5); endometrial cancer, 2.1(1.1–3.9); and breast cancer, 1.4(1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95%CI) to age 70 years for biallelic mutation carriers were: bladder cancer, 25%(5%–77%) for males and 8%(2%–33%) for females; and ovarian cancer, 14%(2%–65%). The cumulative risks (95%CI) for monoallelic mutation carriers were: gastric cancer, 5%(4%–7%) for males and 2.3%(1.7%–3.3%) for females; hepatobiliary cancer, 3%(2%–5%) for males and 1.4%(0.8%–2.3%) for females; endometrial cancer, 3%(2%–6%); and breast cancer 11%(8%–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…MutY DNA glycosylase (MUTYH) excises adenine, which is inappropriately paired. It is known especially for its role in an increased risk of colorectal cancer [134], but its biallelic mutation is also a risk factor for OvC [135]. The role of DNA glycosylases in the therapy outcome of OvC remains unknown.…”

<p>A Novel Mutation in <em>MYH</em> Gene Associated with Aggressive Colorectal Cancer in a Child: A Case Report and Review of Literature</p>

“…18 Patients with a double allele MYH mutation have an almost 80% risk of developing colorectal cancer and an equally high risk of developing adenomatous polyps, while patients with a single allele MYH mutation have an increased risk of colorectal cancer or polyps. 19 Biallelic (homozygous or compound heterozygous) and monoallelic MYH germline mutations have been detected in Caucasian patients with multiple colorectal adenomas having 3-100 polyps. 20 The frequency of biallelic germline mutations of the MYH gene is reported as between 7% and 42% in patients with multiple colorectal adenomas.…”

MUTYH: Not just polyposis

“…Several studies have reported an increased risk of bladder, ovarian, skin, breast and endometrial cancer for biallelic mutation carriers[ 64 , 83 - 85 ] and a slightly increased cumulative risk in MUTYH heterozygotes for gastric, liver, endometrial and breast cancer[ 64 , 84 , 86 , 87 ].…”

“…In this study, silencing of MUTYH using siRNA in a cultured PDAC cell line reduced proliferation, increased apoptosis and finally increased chemo-sensitivity in vitro , suggesting that MUTYH is a novel therapeutic target for pancreatic cancer. PDAC has not or has rarely been reported in MAP patients[ 64 , 65 , 87 ].…”