What is the role of genetic testing in guiding treatment decisions for patients with renal cell carcinoma (RCC)?

Genetic Testing in Renal Cell Carcinoma

Germline genetic testing should be performed in RCC patients who are ≤46 years old, have bilateral or multifocal lesions, have a first- or second-degree relative with RCC, exhibit syndrome-associated features, or have exhausted standard therapeutic options, as approximately 10-17% of these patients harbor pathogenic germline variants that can guide surveillance and treatment decisions. 1

Specific Indications for Germline Testing

The 2024 ESMO guidelines provide clear criteria for when to pursue genetic assessment 1:

• Age ≤46 years at diagnosis - This cutoff captures 70% of hereditary RCC cases, with median age of hereditary RCC being 37 years 1, 2
• Bilateral or multifocal renal tumors - These features are strongly associated with pathogenic variants (P = 0.0012 and P = 0.0098 respectively) 3, 2
• Family history of RCC in first- or second-degree relatives 1, 2
• Syndrome-associated extrarenal manifestations suggesting hereditary conditions 2
• Patients who have exhausted standard therapeutic options - to identify potentially targetable mutations 1

Yield of Genetic Testing

The prevalence of pathogenic/likely pathogenic (P/LP) germline variants varies by population enrichment 4, 3, 5, 6:

• Unselected RCC patients: 10-13% carry P/LP variants 4, 3
• Early-onset RCC (≤46 years): 17.7% carry P/LP variants 5
• Advanced RCC: 16.1% carry germline mutations 6
• Multiple enrichment features: The odds of identifying a germline variant nearly double with each additional enrichment feature (OR 1.82,95% CI: 1.10-3.05) 7

Importantly, 35-45% of patients with P/LP variants have potentially targetable mutations that can guide therapy 3, 5.

Most Common Germline Mutations

The spectrum of mutations identified includes both RCC-specific and other cancer predisposition genes 1, 2:

RCC-associated genes:

• VHL (2.2-3.1%) 1, 4
• FLCN (3.1%) 3
• FH (0.6-2.8%) 1, 4, 6
• SDHB (1.2%) 3
• BAP1 6
• MET, TSC2 4

Other cancer predisposition genes (6.2-8.6% of patients):

• CHEK2 (most frequent non-RCC gene, OR 3.0 for RCC risk) 6
• BRCA1/2 4, 5
• ATM 4, 5
• NBN, BLM 4
• MLH1 3

Clinical Factors Predicting Positive Results

Beyond the ESMO criteria, additional factors increase likelihood of P/LP variants 3, 5, 6:

• Non-clear cell histology - significantly more likely to harbor mutations (11.7% vs 1.7%, P = 0.001) 6
• Female sex - predictive on multivariate analysis (OR 2.80,95% CI: 1.24-6.67) 7
• Multiple extrarenal primary malignancies 5
• Presence of 2-3 enrichment features - 16.4% positive with 2 features, 36.4% with 3 features 7

Critical caveat: In patients with only solitary clear-cell RCC and no other features, the prevalence of RCC-associated gene mutations is 0%, though 9.9% still carry non-RCC cancer predisposition genes 5.

Limitations of Current Guidelines

Current clinical guidelines miss 35.7% of patients with RCC-associated gene mutations 6. This supports a more inclusive approach to genetic testing, particularly since:

• Age and family history alone were not statistically significant predictors in some studies 3
• Approximately 39.3% of patients with P/LP variants show somatic "second hit" events 4
• Combined germline and somatic sequencing provides actionable targets in 17.1% of the entire RCC cohort 4

Therapeutic Implications of Specific Mutations

Actionable germline findings include 2:

• VHL disease: Belzutifan approved for VHL-associated ccRCC not requiring immediate surgery (ORR 49% at 21.8 months, 64% at 37.8 months) 2
• MTOR pathway mutations: Predict sensitivity to everolimus and temsirolimus 2
• MET pathway alterations: Associated with type 1 papillary RCC, may guide MET inhibitor use 2
• ALK rearrangements: Direct use of ALK inhibitors 2

Somatic/Molecular Testing Considerations

While germline testing identifies hereditary risk, somatic molecular classification is increasingly important but not yet routinely required 1:

• The 2022 WHO classification introduced 11 molecular-defined RCC subgroups that cannot be diagnosed by morphology alone 2
• Priority remains identifying established subtypes (ccRCC vs pRCC vs chromophobe) with well-defined treatment algorithms 1
• Sarcomatoid features are increasingly important for systemic therapy consideration 1
• Gene expression panels can identify high-risk disease and angiogenic vs immunogenic tumors, but are not applicable for routine use 1
• PD-L1 has been unreliable as a biomarker in RCC 1

Practical Testing Algorithm

Step 1: Screen for germline testing indications 1, 2:

• Age ≤46 years
• Bilateral/multifocal lesions
• Family history (first- or second-degree relatives with RCC)
• Syndrome features
• Exhausted standard options

Step 2: Consider additional high-risk features 3, 7, 5, 6:

• Non-clear cell histology
• Female sex
• Multiple primary cancers
• Advanced stage at presentation

Step 3: Choose testing approach 3, 5:

• Targeted gene panel if syndromic features present (higher yield: P = 0.015)
• Comprehensive multigene panel (>20 genes) for broader assessment, particularly in early-onset or advanced disease

Step 4: Integrate results with treatment planning 2, 4:

• Identify targetable mutations (VHL, MTOR, MET, ALK)
• Assess for "second hit" somatic events (39.3% of germline carriers)
• Consider combined germline/somatic sequencing for maximal actionable target identification (17.1% yield)