Genetic Testing and Molecular Classification in Renal Cell Carcinoma

Indications for Germline Testing

The European Society for Medical Oncology (ESMO) recommends germline genetic testing for patients diagnosed with renal cell carcinoma (RCC) at a young age (≤46 years), those with multiple or bilateral lesions, patients with first- or second-degree relatives who have had RCC, and those who have exhausted standard therapeutic options 1, 2, 3
Age-based screening is recommended for patients diagnosed at younger ages, as the median age at diagnosis of hereditary RCC is 37 years, with 70% of hereditary cases occurring in patients ≤46 years old 4
Family history of RCC is an indication for genetic testing, particularly for first- or second-degree relatives 1, 2, 3
Tumor characteristics, such as multiple or bilateral renal lesions, are also an indication for genetic testing 1, 2, 3
Syndrome-associated features, such as extrarenal manifestations suggesting hereditary syndromes, are an indication for genetic testing 4

The 2022 WHO classification introduced a molecular-driven approach with 11 subgroups of molecular-defined RCC that cannot be diagnosed by morphology alone 1, 2, 3
Molecular classification based on genome sequencing is recommended, but not yet mandated due to limited availability and lack of actionable targets for most identified mutations 2, 3
Key molecular subtypes with therapeutic implications include eosinophilic solid and cystic RCC, ALK-rearranged RCC, TFEB-altered RCC, SMARCB1-deficient medullary RCC, and FH-deficient RCC 1, 2, 3

Specific mutations, such as PBRM1, BAP1, SETD2, and MTOR, correlate with prognosis in clear cell RCC 5, 6
PBRM1 mutations are associated with stage III pathological features but generally favorable prognosis 5, 6
BAP1 mutations are correlated with larger tumor size, higher nuclear grade, and worse cancer-specific survival 5, 6
SETD2 mutations are associated with increased tumor aggressiveness 5, 6
MTOR mutations are functionally activating mutations that explain efficacy of mTOR inhibitors like everolimus and temsirolimus 6

For VHL disease, belzutifan is approved for VHL-associated ccRCC that does not require immediate surgery, with an objective response rate of 49% at 21.8 months and 64% at 37.8 months 7, 4
MTOR pathway mutations predict sensitivity to mTOR inhibitors (everolimus, temsirolimus) 5, 6
MET pathway alterations are associated with type 1 papillary RCC and may guide use of MET inhibitors 5, 6
ALK rearrangements direct use of ALK inhibitors 1, 2, 3

Screen for germline testing indications: age ≤46 years, family history, bilateral/multiple lesions, syndrome features, or exhausted standard options 1, 2, 3, 4
Establish histologic subtype: priority is ccRCC versus non-ccRCC and presence of sarcomatoid features 2, 3
Consider molecular testing when available: particularly for rare subtypes that cannot be diagnosed morphologically 1, 2, 3
Use molecular data for treatment selection: when actionable targets identified (VHL disease, MTOR mutations, ALK rearrangements) 7, 4, 6
Apply gene expression signatures: for prognostication in localized disease when available 8