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.