What is the role of genetic testing in Renal Cell Carcinoma (RCC) management?

Role of Genetic Testing in Renal Cell Carcinoma

Germline genetic testing is recommended for younger patients (≤46 years), those with multiple or bilateral lesions, patients with first- or second-degree relatives who have had RCC, those with related disorders associated with known predisposing conditions, and those who have exhausted standard therapeutic options. 1

Indications for Germline Testing

The 2024 ESMO guidelines establish clear criteria for when genetic testing should be pursued:

• Age-based screening: Patients diagnosed at younger ages warrant testing, as the median age at diagnosis of hereditary RCC is 37 years, with 70% of hereditary cases occurring in patients ≤46 years old 1
• Family history: First- or second-degree relatives with RCC history 1
• Tumor characteristics: Multiple or bilateral renal lesions 1
• Syndrome-associated features: Presence of extrarenal manifestations suggesting hereditary syndromes 1
• Treatment planning: Patients who have exhausted standard therapeutic options, as molecular profiling may identify actionable targets 1

Approximately 5-8% of RCCs are hereditary or syndrome-related, though this may be an underestimation 1. Chinese cohort data suggests approximately 10% of unselected RCC patients carry pathogenic/likely pathogenic germline variants 2.

Molecular Classification and Somatic Testing

The 2022 WHO classification introduced a molecular-driven approach with 11 subgroups of molecular-defined RCC that cannot be diagnosed by morphology alone 1. While molecular classification based on genome sequencing is recommended, it is not yet mandated due to limited availability and lack of actionable targets for most identified mutations. 1

Key Molecular Subtypes with Therapeutic Implications:

• Eosinophilic solid and cystic RCC (TSC mutation/mTOR pathway activation): Responds to mTOR inhibitors 1
• ALK-rearranged RCC: Responds to ALK inhibitors 1
• TFEB-altered RCC: TFEB-translocated forms are typically indolent; TFEB-amplified forms are highly aggressive 1
• SMARCB1-deficient medullary RCC: Highly aggressive subtype 1
• FH-deficient RCC: May be associated with hereditary leiomyomatosis and RCC syndrome 1

Prognostic Gene Mutations in Clear Cell RCC

Beyond VHL gene alterations (present in the vast majority of sporadic ccRCC), specific mutations correlate with prognosis 1, 3:

• PBRM1 mutations (29-41% of tumors): Associated with stage III pathological features but generally favorable prognosis 1, 3
• BAP1 mutations (6-10%): Correlated with larger tumor size, higher nuclear grade, and worse cancer-specific survival 1, 3
• SETD2 mutations (8-12%): Associated with increased tumor aggressiveness 1, 3
• MTOR mutations (5-6%): Functionally activating mutations that explain efficacy of mTOR inhibitors like everolimus and temsirolimus 3

VHL mutation status alone has no effect on clinical outcome as it is the founding event of ccRCC. 3

Therapeutic Applications

Hereditary RCC Management:

For VHL disease, belzutifan is approved for VHL-associated ccRCC that does not require immediate surgery. 1 This approval was based on a phase 2 trial showing 49% objective response rate at 21.8 months, increasing to 64% at 37.8 months 1.

Targeted Therapy Selection:

• MTOR pathway mutations: Predict sensitivity to mTOR inhibitors (everolimus, temsirolimus) 1, 3
• MET pathway alterations: Associated with type 1 papillary RCC, may guide use of MET inhibitors 1, 3
• ALK rearrangements: Direct use of ALK inhibitors 1

Current Limitations and Practical Considerations

When genome sequencing is not available, pathologists should provide detailed morphological descriptions with comments regarding possible molecular alterations. 1 The priority remains identifying ccRCC versus papillary RCC or other established subtypes, and detecting sarcomatoid features 1.

Common Pitfalls:

• Current guideline recommendations for genetic testing may not be sensitive enough to identify all patients with hereditary RCC susceptibility 2
• Many laboratories still lack access to comprehensive molecular testing 1
• Most identified targets are not currently actionable 1
• Heterogeneity between primary tumor and metastases can complicate interpretation 1

Gene Expression Signatures

Gene signatures like ClearCode34 (34-gene panel) can classify ccRCC into subtypes (ccA and ccB) significantly associated with relapse-free survival and overall survival. 1 A 16-gene assay improved prediction of recurrence-free survival compared to the SSIGN score (concordance: 0.81 versus 0.74) 1.

Practical Algorithm

1. Screen for germline testing indications: Age ≤46 years, family history, bilateral/multiple lesions, syndrome features, or exhausted standard options 1
2. Establish histologic subtype: Priority is ccRCC versus non-ccRCC and presence of sarcomatoid features 1
3. Consider molecular testing when available: Particularly for rare subtypes that cannot be diagnosed morphologically 1
4. Use molecular data for treatment selection: When actionable targets identified (VHL disease, MTOR mutations, ALK rearrangements) 1, 3
5. Apply gene expression signatures: For prognostication in localized disease when available 1