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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.

SUBMITTER: Bakouny Z

PROVIDER: S-EPMC7865061 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Sarcomatoid differentiation in renal cell carcinoma (RCC) with vena caval tumour thrombus has been shown to be associated with aggressive behaviours and poor prognosis; however, evidence of the impact of rhabdoid differentiation on prognosis is lacking. This study evaluated the impact of sarcomatoid differentiation and rhabdoid differentiation on oncological outcomes for RCC with vena caval tumour thrombus treated surgically. METHODS:We retrospectively analysed patients treated surgically for RCC with vena caval tumour thrombus at our institute from Jan 2015 to Nov 2018. Prognostic variables were evaluated for associations with progression-free survival (PFS) and cancer-specific survival (CSS) by Kaplan-Meier survival analysis and log-rank test. Univariate and multivariate analyses were performed to determine independent prognostic variables. RESULTS:We identified 125 patients with RCC and vena caval tumour thrombus, including 17 (13.6%) with sarcomatoid differentiation alone, 8 (6.4%) with rhabdoid differentiation alone and 3 (2.4%) with both sarcomatoid and rhabdoid differentiation. Compared to pure RCC, patients with sarcomatoid differentiation but not rhabdoid differentiation have worse PFS (p?=?0.018 and p?=?0.095, respectively). The univariate and multivariate analyses both showed sarcomatoid differentiation as a significant predictor of PFS. Compared to pure RCC, patients with sarcomatoid differentiation (p?=?0.002) and rhabdoid differentiation (p?=?0.001) both had significantly worse CSS. The univariate analysis showed sarcomatoid differentiation, rhabdoid differentiation, metastasis and blood transfusion as significant predictors of CSS (All, p?<?0.05). In the multivariate analysis, sarcomatoid differentiation (HR 3.90, p?=?0.008), rhabdoid differentiation (HR 3.01, p?=?0.042), metastasis (HR 3.87, p?=?0.004) and blood transfusion (HR 1.34, p?=?0.041) all remained independent predictors of CSS. CONCLUSIONS:Sarcomatoid differentiation and rhabdoid differentiation are both independent predictors of poor prognosis in RCC with vena caval tumour thrombus treated surgically.

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Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

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