Molecular characterization of chromophobe renal cell carcinoma reveals mTOR pathway alterations in patients with poor outcome
| Autor: | Luis J Leandro-García, Guillermo Velasco, Bruna Calsina, Georgia Anguera, Pablo Maroto, Rocío Letón, Maria José Santos, María Monteagudo, Ángel M Martínez-Montes, Eduardo Caleiras, Jesús García-Donas, Cristina Rodríguez-Antona, Cristina Montero-Conde, Alberto Cascón, Javier Lanillos, Mercedes Robledo, Juan María Roldan-Romero |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Pathology medicine.medical_specialty DNA Mutational Analysis Chromophobe Renal Cell Carcinoma medicine.disease_cause Tuberous Sclerosis Complex 1 Protein Pathology and Forensic Medicine Metastasis 03 medical and health sciences 0302 clinical medicine Tuberous Sclerosis Complex 2 Protein Biomarkers Tumor Carcinoma Humans Medicine PTEN Genetic Predisposition to Disease Phosphorylation Carcinoma Renal Cell PI3K/AKT/mTOR pathway Survival analysis Aged Aged 80 and over Mutation biology business.industry Ribosomal Protein S6 Kinases TOR Serine-Threonine Kinases PTEN Phosphohydrolase High-Throughput Nucleotide Sequencing Middle Aged medicine.disease Immunohistochemistry Kidney Neoplasms Phenotype 030104 developmental biology 030220 oncology & carcinogenesis biology.protein Cancer research Female Tumor Suppressor Protein p53 business |
| Zdroj: | MODERN PATHOLOGY r-IIB SANT PAU: Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau Institut dInvestigació Biomèdica Sant Pau (IIB Sant Pau) r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau instname |
| ISSN: | 0893-3952 |
| DOI: | 10.1038/s41379-020-0607-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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