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// Michelangelo Fiorentino 1 , Elisa Gruppioni 1 , Francesco Massari 2 , Francesca Giunchi 1 , Annalisa Altimari 1 , Chiara Ciccarese 7 , Davide Bimbatti 6 , Aldo Scarpa 8 , Roberto Iacovelli 7 , Camillo Porta 9 , Sarhadi Virinder 4 , Giampaolo Tortora 7 , Walter Artibani 6 , Riccardo Schiavina 3 , Andrea Ardizzoni 2 , Matteo Brunelli 5 , Sakari Knuutila 4,* and Guido Martignoni 5,* 1 Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy 2 Department of Medical Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy 3 Department of Urology, S.Orsola-Malpighi Hospital, Bologna, Italy 4 Department of Pathology, University of Helsinki, Faculty of Medicine, Helsinki, Finland 5 Department of Pathology, Diagnostics and Public Health University of Verona, Verona, Italy 6 Department of Urology, Diagnostics and Public Health University of Verona, Verona, Italy 7 Department of Medical Oncology, Diagnostics and Public Health University of Verona, Verona, Italy 8 Diagnostics and Public Health University of Verona, Verona, Italy 9 Department of Medical Oncology, University of Pavia, Pavia, Italy * These authors co-shared senior authorship Correspondence to: Michelangelo Fiorentino, email: // Keywords : renal cell carcinoma, next generation sequencing, target therapy, metastatic disease, VHL, Pathology Section Received : July 06, 2016 Accepted : September 21, 2016 Published : October 10, 2016 Abstract Renal cell cancer (RCC) is characterized by histological and molecular heterogeneity that may account for variable response to targeted therapies. We evaluated retrospectively with a next generation sequencing (NGS) approach using a pre-designed cancer panel the mutation burden of 32 lesions from 22 metastatic RCC patients treated with at least one tyrosine kinase or mTOR inhibitor. We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes. Somatic alterations were correlated with response to therapy. Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each). Eight (36%) patients were wild-type at least for the genes included in the panel. A genotype concordance between primary RCC and its secondary lesion was found in 3/6 cases. Patients were treated with Sorafenib, Sunitinib and Temsirolimus with partial responses in 4 (18,2%) and disease stabilization in 7 (31,8%). Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants. Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A . Among the 11 non-responders 7 (64%) were wild-type, 2 (18%) were p53 mutated and 2 (18%) VHL1 mutated. No significant associations were found among RCC histotype, mutation variants and response to therapies. In the absence of predictive biomarkers for metastatic RCC treatment, a NGS approach may address single patients to basket clinical trials according to actionable molecular specific alterations.

Renal cell carcinoma (RCC) is a metabolic disease, being characterized by the dysregulation of metabolic pathways involved in oxygen sensing (VHL/HIF pathway alterations and the subsequent up-regulation of HIF-responsive genes such as VEGF, PDGF, EGF, and glucose transporters GLUT1 and GLUT4, which justify the RCC reliance on aerobic glycolysis), energy sensing (fumarate hydratase-deficient, succinate dehydrogenase-deficient RCC, mutations of HGF/MET pathway resulting in the metabolic Warburg shift marked by RCC increased dependence on aerobic glycolysis and the pentose phosphate shunt, augmented lipogenesis, and reduced AMPK and Krebs cycle activity) and/or nutrient sensing cascade (deregulation of AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR pathways). We analyzed the key metabolic abnormalities underlying RCC carcinogenesis, highlighting those altered pathways that may represent potential targets for the development of more effective therapeutic strategies.