EURURO Vol. 72 No. 5

658 860

association studies (GWAS) led to the successful identifica-
tion of >100 SNPs associated with prostate cancer risk.
Although the relative increase in risk for any single SNP is
small, the risk increases as the number of inherited risk
SNPs increases, but SNPs appear to explain only approxi-
mately 25% of the risk associated with a positive family
history, and the clinical utility of these findings remains
uncertain.
5. Where is the missing heritability?
Going back to the drawing board, but this time armed with
high-throughput next-generation sequencing (NGS), we
again searched for rare variants in the hope that there might
be multiple rare variants that contribute a large effect.
5.1. HOXB13
Our first use of NGS was in collaboration with investigators
at the University of Michigan, who had reported linkage at
17q21. We identified one missense variant mutation in
homeobox gene HOXB13, involving a change from glycine to
glutamine at codon 84 (G84E), which turned out to be a
founder mutation in men of Nordic descent . This gene is
known to be prostate-specific in its expression pattern, and
in mice it plays a critical role in the development and
maintenance of normal prostate function. This time,
confirmatory studies involving many thousands of men
unequivocally established HOXB13 as the first validated
gene associated with prostate cancer susceptibility.
5.2. BRCA1/2, DNA repair, and mismatch repair mutations
Some 20 yr ago, studies in Icelandic families implicated
BRCA2 as an important gene for prostate cancer; more
recently, Eeles and her research group at the Royal
Marsden provided additional evidence that defective
BRCA2 genes are associated with an inherited risk of more
aggressive prostate cancer . However, we recently
learned of its impact on the development of castration-
resistant prostate cancer (CRPC). A study by the Stand Up
to Cancer research group, which carried out the first in-
depth sequencing in men with CRPC, demonstrated that 6%
of men with CRPC had deleterious germline mutations of
BRCA2 . When coupled with other genes involved in
DNA repair (such as ATM and the mismatch repair genes in
Lynch syndrome, eg MSH2) the total number of CRPC
patients with inherited mutations rose to >12%. In a study
at Johns Hopkins, together with our colleagues at North-
Shore, we found that among men who died from prostate
cancer before age 65 yr, 10–12% carried mutations in
BRCA2/BRCA1 and ATM
6. Clinical implications
Family history is a major risk factor for development of
the disease. The history should include age at diagnosis
of prostate cancer in both paternal and maternal lineages,
and a complete list of other cancers. Factors suggestive of
a genetic contribution to prostate cancer include the
following: (1) multiple affected first-degree relatives with
prostate cancer, including three successive generations
with prostate cancer in the maternal or paternal lineage; (2)
early-onset prostate cancer (age 55 yr); and (3) prostate
cancer with a family history of the BRCA1/2 mutation or
other cancers (eg, breast, ovarian, pancreatic).
7. Who should be referred to a genetic counselor
for genetic testing?
HOXB13: men of Nordic descent, who are up to five to ten
times more likely to carry the mutation.
BRCA 1/2: men with a personal history of Gleason
7 prostate cancer with a family history of a BRCA1/2
mutation, or one close relative with ovarian or breast
cancer at age <50 yr, or two relatives with breast,
pancreas, or Gleason 7 prostate cancer at any age.
DNA repair mutations: men with CRPC to identify
patients for treatment with PARP inhibitors or platinum
rather than taxanes, and to inform family members.
8. Have we been looking in the wrong place?
No one knows for sure, but on the basis of the recent
discovery that patients with lethal and aggressive prostate
cancer who do not have a strong family history can carry
DNA repair mutations in their germline, it is possible that
we have been looking at the wrong patients. Our studies
have always concentrated on men with multiple affected
family members who are alive. Instead, if future studies
concentrate on patients with lethal and advanced disease, it
is possible we will uncover many previously unknown
important pathways.
9. Conclusion
In closing, it is important to emphasize that this effort has
been led by Dr. William Isaacs, who has dedicated his skill,
intellect, and energy for the last three decades to uncover
the genetic pathogenesis of prostate cancer working with
our co-investigators from the University of Michigan, the
NorthShore University Health System, the Translational
Genomics Research Institute, the University of North
Carolina, and the International Consortium for Prostate
Cancer Genetics.
Conflicts of interest: The author has nothing to disclose.
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