Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma

Abstract

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

Efficacy and correlative analyses of avelumab plus axitinib versus sunitinib in sarcomatoid renal cell carcinoma: post hoc analysis of a randomized clinical trial

“…Additionally, this observation is consistent with findings from a recent molecular characterization study of rhabdoid and sRCC tumors from both clinical trials and real-world cohorts, which reported that these tumors have an immune-inflamed phenotype with increased immune activation, CD8+ T-cell infiltration, and PD-L1 expression. 20 Another notable finding in our study was that angiogenesis-related genes and signatures had limited association with prolonged PFS in the combination arm, and the expression of genes associated with hypoxia and glycolytic pathway activation were not associated with prolonged PFS. Further studies are needed to determine whether ICI monotherapy would provide similar benefits to combination ICI and TKI therapy in this population.…”

“… 16 , 17 , 18 , 19 Additionally, a recent study evaluating the molecular characterization of rhabdoid and sRCC tumors reported that these tumors are highly responsive to ICI treatment and have an immune-inflamed microenvironment, which may help drive this responsiveness. 20 Here, we report results from a post hoc analysis of patients enrolled in the JAVELIN Renal 101 trial whose tumors had sarcomatoid features, including correlative gene expression analyses.…”

The Molecular Characteristics of Non-Clear Cell Renal Cell Carcinoma: What’s the Story Morning Glory?

“…First of all, S/R RCCs are characterized by the enrichment of MYC-regulated genes, along with multiple molecular pathways involved in cell cycle regulation and tumor's invasiveness. The upregulation of these MYC-related genes correlates with the poor quoad vitam prognosis of these histotypes, thus unveiling its pathogenetic key role as molecular driver of aggressivity of S/R RCCs [35]. According to prior studies, several mutations regarding the Hippo pathway (including NF2 gene's ones) have been marked in sarcomatoid RCC, while BAP1 abnormalities have been shown to relate to sarcomatoid as well as rhabdoid RCC tumors.…”

“…Both the sarcomatoid and epithelial components of the neoplasia share a common progenitor cell, but the clonal evolution during the oncogenesis leads to several genetic abnormalities in cells that are going to take part of the sarcomatoid component, triggering the so-called epithelial-to-mesenchymal transition (EMT) and hesitating in intratumoral genetic heterogeneity [34]. An expanded clinical and molecular integrated characterization of S/R RCC, built on data from clinical trials and real-world cohorts, has been recently carried out by Bakouny and colleagues, shedding light on the molecular drivers of aggressivity and responsiveness to therapies of these so far little known histotypes [35]. First of all, S/R RCCs are characterized by the enrichment of MYC-regulated genes, along with multiple molecular pathways involved in cell cycle regulation and tumor's invasiveness.…”

“…S/R RCC cells display an overexpression of all 8 "Hallmark" immune gene sets (including IL6-JAK-STAT3 signaling and IF gamma response). Moreover, an immune responsive microenvironment is significantly expressed in S/R RCC tumors, including elements such as M1 macrophages, Th1 T cell subsets, or activated NK cells [35]. Lastly, mutations in specific tumor suppressor genes (in particular TP53, but also ARID1A) are described as very common findings in sarcomatoid and rhabdoid components of S/R RCCs [40].…”