Clinical utility of Germline and Somatic Testing:
In the era of precision medicine, genetic testing is widely considered
in clinical practice as it helps to tailor the treatment for complex and
heterogeneous diseases such as prostate cancer. By sequencing the tumor
genome with NGS, actionable biomarkers can be
identified51.
With approximately 5%-10% of mutations being germline
mutations56, germline testing is essential in
identifying risk biomarkers or germline mutations that are associated
with increased cancer susceptibility. In the setting of PCa, the highest
risk levels was reported in the presence of homologous recombination
repair (HRR) gene BRCA1/2, which confers a 4-8 fold increase in
risk32 57, followed by the presence
of HOXB13 mutation, a gene encoding homeobox transcription factor B13,
which has been associated with a 4 fold increase in
susceptibility58 59. Studies have
also shown that pathogenic mutations in BRCA1/2 and HOXB13 increase the
risk for earlier onset of PCa57. Men with DNA mismatch
repair gene mutations (MLH1, MSH2, and MSH6 ) have a 2-4
fold greater susceptibility to develop PCa60. Emerging
data suggests that NBS1, FANCA and other DNA repair genes are associated
with increased PCa risk and choice of treatment61.
The implications of germline and somatic mutation expand to being able
to act as a molecular target for several drugs. For example, TOPARP- A
Trial62 have demonstrated improved response to the
PARP inhibitor (PARPi), Olaparib, among men with metastatic castrate
resistant prostate cancer (mCRPC) harboring DNA-repair defects
(BRCA1/2 and ATM). Following this trial, the United States Food and Drug
Administration granted Breakthrough Therapy designation to Olaparib.
Also, the presence of BRCA1/2 and other DNA repair genes have been
associated with improved response to platinum-based chemotherapy, and
the presence of DNA mismatch repair genes have been associated with
response to anti-PD-1 immunotherapy6364. With new
advances, more clinically actionable mutations will appear and more
diagnostic and therapeutic implications for somatic and germline testing
would emerge (Figure 2). Continued efforts are needed to determine if
these emerging targeted therapies have the same clinical utility in
diverse populations.