Renal cell carcinoma (RCC) encompasses a heterogeneous group of tumors classified into distinct histological subtypes (Figure 1). The most frequent is clear cell RCC (ccRCC), whereas less common forms include papillary RCC, chromophobe RCC, FH-deficient and SDH-deficient RCC, as well as tumors with gene fusions involving TFE3, TFEB, or ALK. These tumor subtypes differ in morphology, harbor specific molecular alterations, and are associated with distinct clinical outcomes.
Figure 1. Histological and molecular classification of renal cell carcinoma subtypes with their characteristic genetic alterations. The pie chart illustrates the relative frequency distribution of renal cell carcinoma (RCC) subtypes based on histopathological and molecular characteristics. Clear cell RCC represents the most common subtype (75% of cases), characterized by distinctive clear cytoplasm due to lipid and glycogen accumulation, and is primarily driven by VHL gene inactivation leading to HIF pathway dysregulation. Additional frequent mutations include chromatin remodeling genes (PBRM1, SETD2, BAP1, KDM5C), mTOR pathway components, and the tumor suppressor TP53. Papillary RCC accounts for 10% of cases and was historically subdivided into type 1 (classic) and type 2. It is a heterogeneous group with biphasic and reverse polarity variants. Characteristic alterations in MET, NF2, and the NRF2-ARE antioxidant pathway. Chromophobe RCC (5% of cases) typically harbors TP53 and PTEN mutations along with mitochondrial DNA defects and mTOR pathway alterations. Molecularly defined entities (collectively ~5%): FH-deficient RCC (FH mutations), SDH-deficient RCC (SDH complex mutations), translocation RCC (TFE3/TFEB fusions), ALK-rearranged RCC (ALK fusions), ELOC-mutated RCC (ELOC mutations), SMARCB1-deficient medullary carcinoma (SMARCB1 loss), and collecting duct carcinoma. Unclassified RCC represents 3-4% of cases that do not fit established histological or molecular criteria. The histological image shows representative clear cell RCC morphology with characteristic clear cytoplasm and prominent vasculature. Understanding these molecular alterations is crucial for precision medicine approaches, as different subtypes respond variably to targeted therapies including VEGFR inhibitors, immune checkpoint blockade, and mTOR inhibitors.
We propose that the limited efficacy of current first-line treatments in many patients with rare kidney tumors stems from a lack of molecular rationale. For instance, tumors with minimal hypoxia signaling or low immune cell infiltration are likely to respond poorly to antiangiogenic agents and immunotherapy. Clinical trials in kidney cancer patients often combine multiple RCC histologies with diverse oncogenic drivers, yielding imprecise average responses with limited translational value. Moreover, as is common in rare or low-frequency diseases, recruiting metastatic “non–clear cell RCC” patients is challenging, and industry-sponsored, histology-specific trials are scarce. Consequently, metastatic disease in patients with rare kidney tumors remains poorly studied, managed with non-specific therapies that frequently produce variable and suboptimal outcomes.
1) Chromophobe renal cell carcinoma
Our recent work on chromophobe RCC proposed mTOR pathway as a promising therapeutic target in a subset of metastatic patients (Mod Pathol 2020, PMID 32616874; Figure 2A), defined how mutations in this pathway modulate the response of patients to mTOR inhibitors (JNCCN 2017 and 2018, Int J Cancer 2020; PMIDs 29118224, 29632054, 31335987) and discovered USP9X as a novel therapeutic target with synthetic lethality with mTOR inhibitors (Int J Cancer 2023, PMID 37260183; Figure 2B).
Our current studies aim to extend these findings and investigate a potential interaction between mTOR pathway and mitochondrial mutations in the electron transport chain.
Figure 2. Somatic alterations in chromophobe RCC tumors and their connection with mTOR inhibitor treatment. A) Oncoprint showing that mTOR pathway activation is detected in 17% of chRCC and is associated with poor overall survival (OS). Adaptation from Roldan-Romero et al. 2020 Mod Pathol; PMID 32616874. B) Whole Exome Sequencing of three chRCC metastatic patients with extraordinary response to the mTOR inhibitor temsirolimus reveals USP9X loss as the only shared somatic mutational event. USP9X loss is defined as the molecular determinant of drug sensitivity, through dysregulated autophagy, which has a synergistic effect with mTOR inhibition. Adaptation from Roldan-Romero et al. 2023 Int J Cancer; PMID 37260183.
2) Papillary renal cell carcinoma
In papillary RCC, we have identified a molecular subgroup—representing 31% of cases—characterized by overactivation of the HIF pathway (“HIF-active”). These tumors exhibit high hypoxia scores, enhanced angiogenesis, reduced expression of Krebs cycle genes and mitochondrial activity, elevated immune cell infiltration, and increased epithelial-mesenchymal transition, all of which are associated with higher metastatic risk and poorer overall survival.
Metabolomic analyses revealed that the pseudohypoxia in HIF-active tumors is driven by accumulation of the oncometabolite L-2-hydroxyglutarate (L-2-HG), which inhibits HIF prolyl hydroxylases and prevents HIFα degradation. We propose that this novel definition of a pseudohypoxic pRCC subgroup with HIF-pathway overactivation will deepen our understanding of pRCC heterogeneity and provide potential insights into differential responses to targeted therapies (de Nicolás et al. 2025 bioRxiv; doi: 0.1101/2025.01.24.632989; Figure 3).
Figure 3. Model illustrating the mechanism of L-2-HG accumulation in pRCC and the subsequent effects that define HIF-active pRCC characteristics. L-2-HG accumulates due to reduced L2HGDH activity, preventing conversion to α-ketoglutarate. Accumulated L-2-HG competitively inhibits α-ketoglutarate-dependent dioxygenases including HIF prolyl hydroxylases (PHDs), lysine demethylases (KDMs), and TET enzymes. This inhibition stabilizes HIF-1/2α, alters histone methylation, and causes DNA hypermethylation, creating a pseudohypoxic state. The resulting tumor microenvironment in pRCC exhibits enhanced aggressiveness, increased angiogenesis, and altered immune infiltration, contributing to the aggressive phenotype associated with L-2-HG-driven oncometabolism.
3) FH-deficient renal cell carcinoma
In recent years, we have employed targeted NGS panels to investigate the impact of germline mutations in metastatic RCC. A key finding was the high frequency of FH mutations—approximately 20%—in apparently sporadic papillary RCC cases (Santos et al., Genet Med 2021, PMID 37293154). Novel therapies for FH-deficient RCC (FH-RCC), such as the combination of bevacizumab and erlotinib, have recently demonstrated substantial activity in metastatic patients.
Our current research focuses on elucidating the molecular mechanisms that determine FH-RCC and pRCC sensitivity to these targeted treatments.