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© The Canadian Journal of Urology™; 23(2); April 2016
8249
Prostate cancer is one of the most highly heritable
cancers, with an overall estimated inherited component
of ~40%-50%.
2,3
Approximately 5%-10% of inherited
prostate cancers are accounted for by rare mutations
in highly penetrant genes. Family studies and next-
generation sequencing approaches have identified
subsets of prostate cancer associated with germline
mutations in
BRCA1
,
BRCA2
, and
HOXB13
.
4
BRCA1
and
BRCA2
mutations have been associated with a
strong family history of breast cancer, ovarian cancer,
prostate cancer, pancreatic cancer, and/or melanoma as
part of hereditary breast and ovarian cancer syndrome
(HBOC).
5
Furthermore,
BRCA2
mutations have been
associated with a more aggressive prostate cancer
phenotype.
6,7
Arecurrentmutation in
HOXB13
has been
associated with an approximate 2 to 8-fold increase in
risk for hereditary prostate cancer (HPC), the features
of which include generational prostate cancer, multiple
first-degree relatives with prostate cancer, or prostate
cancer diagnosed at age <=55 years.
4,8-10
Furthermore,
molecular studies of prostate cancer have estimated
prostate cancer risk of over 3-fold in DNA mismatch
repair gene mutation carriers associated with Lynch
syndrome, which is characterized by a strong family
history of multiple cancers including colorectal cancer,
ovarian cancer, uterine cancer, gastric cancer, and/
or sebaceous adenocarcinoma.
11
Figure 1a, 1b and 1c
highlights examples of familial cancer features indicative
of HBOC, HPC, and Lynch syndrome where the
presenting patient (proband) is a patient with prostate
cancer. Though clinical genetic testing is available for the
genes linked with HBOC, HPC, and Lynch syndrome,
guidelines supporting genetic testing for prostate cancer
probands are limited and are emerging secondarily from
other cancer syndromes (such as hereditary breast and
ovarian cancer guidelines) which poses challenges for
insurance coverage and subsequent implementation
of genetic testing. However, when inherited prostate
cancer is suspected, referral to genetic counseling is
critical to assess cancer risk, provide patients with
Giri ET AL.
Figure 1c.
Suspected Lynch syndrome pedigree showing the proband (with arrow) with prostate cancer diagnosed
at 60, brother with colon cancer diagnosed at 40, mother with uterine cancer diagnosed at 58, and maternal uncle
with colon cancer diagnosed at 50.