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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
Published on: January 22, 2013
Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor
Juan María Roldan-Romero1, María Santos1, Javier Lanillos1
1Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Abstract:
Chromophobe renal cell carcinoma (chRCC) is a histologically and molecularly distinct class of rare renal tumor. TCGA studies revealed low mutational burden, with only TP53 and PTEN recurrently mutated, and discovered alterations in TERT promoter and in the electron transport chain Complex I genes. However, knowledge on drug targetable genes is limited and treatments at metastatic stage do not follow a molecular rationale. In a large series of 92 chRCC enriched with metastatic cases, we performed an in-depth characterization of mTOR pathway alterations through targeted NGS and immunohistochemistry (IHC) of phospho-S6, tuberin, and PTEN. Mutations in mitochondria, telomere maintenance and other renal cancer related genes and p53 IHC, were also assessed. The impact on metastasis development and disease specific survival was determined, using TCGA-KICH series (n = 65) for validation. mTOR pathway mutations (MTOR, TSC1, TSC2) were present in 17% of primary tumors, most of them being classified as pathogenic. Mutations were associated with positive IHC staining of phospho-S6 and PTEN (P = 0.009 and P = 0.001, respectively) and with chRCC eosinophilic variant (P = 0.039), supporting a biological relevance of the pathway. mTOR pathway mutations were associated with worse clinical outcomes. Survival analysis gave a hazard ratio of 5.5 (P = 0.027), and this association was confirmed in TCGA-KICH (HR = 10.3, P = 0.006). TP53 mutations were enriched in metastatic cases (P = 0.018), and mutations in telomere maintenance genes showed a trend in the same direction. p53 IHC staining pattern was associated with the underlying TP53 defect, and negative PTEN IHC staining (82% of cases) suggested PTEN loss as a chRCC hallmark. In conclusion, our study provides with novel genomic knowledge in chRCC and identifies novel markers of poor survival. Furthermore, this is the first study showing that mTOR pathway mutations correlate with poor prognosis, and may help to identify patients with increased sensitivity to mTOR inhibitors.
Insights
Chromophobe renal cell carcinoma (chRCC) harbors mTOR pathway mutations linked to poor prognosis and metastasis. This study identifies mTOR pathway alterations as potential therapeutic targets for chRCC patients, improving survival outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Chromophobe renal cell carcinoma (chRCC) is a rare kidney cancer with limited understanding of its molecular drivers and drug targets.
- Previous studies identified TP53 and PTEN mutations and alterations in TERT promoter and Complex I genes, but drug targetable genes remain largely unknown.
- Effective treatments for metastatic chRCC are lacking, highlighting the need for molecularly-guided therapeutic strategies.
Purpose of the Study:
- To investigate the role of the mTOR pathway in chRCC pathogenesis and its association with clinical outcomes.
- To identify novel genomic alterations and biomarkers for predicting metastasis and survival in chRCC.
- To explore the potential of mTOR pathway inhibitors as a targeted therapy for chRCC.
Main Methods:
- Targeted next-generation sequencing (NGS) and immunohistochemistry (IHC) were used to analyze mTOR pathway alterations (MTOR, TSC1, TSC2) in 92 chRCC tumors.
- Analysis included IHC for phospho-S6, tuberin, and PTEN, alongside assessment of mutations in mitochondria, telomere maintenance, and TP53.
- Survival analysis and metastasis development were evaluated, with validation using the TCGA-KICH dataset.
Main Results:
- MTOR pathway mutations were identified in 17% of primary chRCC tumors and were associated with positive phospho-S6 and PTEN IHC staining and the eosinophilic variant.
- MTOR pathway mutations significantly correlated with worse clinical outcomes, showing a hazard ratio of 5.5 in the primary cohort and 10.3 in the TCGA-KICH validation cohort.
- TP53 mutations were enriched in metastatic cases, and PTEN loss (negative IHC staining in 82% of cases) was identified as a potential hallmark of chRCC.
Conclusions:
- This study provides novel genomic insights into chRCC, identifying mTOR pathway mutations as a significant indicator of poor prognosis.
- The findings suggest that mTOR pathway alterations may serve as predictive biomarkers for identifying chRCC patients who could benefit from mTOR inhibitors.
- The research highlights the potential for molecularly targeted therapies in chRCC and identifies PTEN loss as a characteristic feature of this rare tumor type.
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