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 analyzed 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.
