The human genome was fully sequenced in April of 2003. At the time, this achievement was a feat of science compared with landing on the moon, but it laid the groundwork for actionable patient data that are being used in 2025 to drive patient care. There is growing evidence to support expanded germline testing and somatic testing for all urologic malignancies, and testing has been incorporated into guidelines.¹ Somatic testing interrogates tumor tissue for acquired mutations that are molecular drivers of the patient’s cancer and may guide targeted therapies. Germline testing on the other hand examines normal tissue for inherited mutations that predispose individuals to cancer. Recent work has demonstrated that universal germline testing reveals a pathologic variant in 1 of 8 patients with a genitourinary (GU) malignancy. Fifty-seven percent of prostate, 100% of bladder, and 78% of renal cancer patients would not have been tested as per guidelines.² Assessment can aid in therapy selection, risk assessment, screening, and prevention for both the patient and family members. In many cases, performing these 2 tests in parallel provides the most comprehensive understanding of the genetic landscape of the patient’s tumor and maximizes clinical decision-making.

Somatic testing is increasingly recommended for advanced or metastatic solid tumors due to the potential for biomarker-informed management that improves progression-free and overall survival.^3,4 The most frequent and relevant biomarkers for GU cancers include mutations in specific genes. For prostate cancer, both germline and somatic DNA repair genes mutations inform eligibility for Food and Drug Administration–approved targeted therapies, namely PARP inhibitors.⁴ PARP inhibitors inhibit the ability of the cancer cell to survive if and only if it has defects in DNA repair. FGFR alterations (mutations, amplification, fusions) have been proven critical in driving bladder/urothelial cancer, and can be targeted with erdafitinib.³ Lastly in renal carcinoma, targeted therapies such as HIF inhibitors for VHL-driven and MET inhibitors for MET-driven tumors can be utilized even for localized disease.⁵

While some mutations are tumor specific, therapies are increasingly driven by molecular markers and not by specific cell of origin. Tumor-agnostic biomarkers, such as MSI-H/dMMR, NTRK fusions, BRAF V600 mutations, RET alterations, HER2 overexpression, and TMB-H, have revolutionized cancer treatment by enabling targeted therapies regardless of tissue origin.⁶ These therapeutic advancements reinforce the need for comprehensive molecular profiling of metastatic/locally advanced GU cancers through next-generation sequencing and immunohistochemistry to identify these actionable alterations and match patients with potentially effective treatments.

At the current time germline testing is recommended for all patients with locally advanced, high-grade, or metastatic prostate cancer. While guidelines may differ slightly, in general, germline testing is also recommended in men with lower-risk disease who have young age of onset (<50 years of age), family members who died of prostate cancer, multiple family members with prostate cancer, and family history of other related malignancies such as breast, ovarian, and pancreatic cancer.¹ The strongest associations have been with the DNA repair pathway, which puts men at increased risk for cancer and in particular aggressive cancer. Some of the more common examples include BRCA2, BRCA1, ATM, and CHECK2.⁷ At this time the benefit is mostly to family members, who should undergo enhanced screening with PSA and MRI.

For kidney cancer, 5% to 8% of cases are attributed to a hereditary component, with at least 15 known genes implicated. However, given that 10% to 25% of patients have multifocal tumors, and 60% of patients in an Icelandic study had a first- or second-degree relative with kidney cancer, the proportion of cases with hereditary influence may be underappreciated. Current guidelines recommend genetic evaluation for patients diagnosed < 46 years old, with multifocal masses, or with close relatives with renal cancer.⁸ Patients with hereditary kidney cancer often have gene-specific surveillance and treatment algorithms. For example, patients with FLCN alterations may undergo active surveillance until tumors reach 3 cm while those with FH alteration are not active surveillance candidates.⁹

Traditionally bladder cancer has been considered to result primarily from exposure to environmental carcinogens such as smoking. Increasingly, however, a hereditary component has been recognized. Across 3 different studies, germline mutations were identified in approximately 20% of patients with bladder cancer, including patients with high-grade but not low-grade nonmuscle-invasive bladder cancer. Lynch syndrome, which is due to alterations in mismatch repair genes such as MSH2, is the best described genetic predisposition for bladder cancer. There is a link also to DNA damage repair genes such as BRCA1 and BRCA2. Definitive guidelines to test patients for germline mutations do not exist, but there is general consensus that young patients (eg, <45 years), those with strong family histories of any cancer, and those with cancers related to Lynch syndrome (especially colorectal and endometrial cancer) should be tested.¹⁰

The future may be universal germline testing. This is already the standard of care for breast, ovarian, pancreatic, colorectal, and now endometrial cancer. Urologic cancers are likely not far behind.² Ultimately, implementing successful genetic testing practices is a multidisciplinary effort that will require advances in physician education, as well as efficient technology-driven delivery models to help scale testing to ensure that all patients and families are receiving maximal benefit.