title: Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach.
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.
authors.affiliation: Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gruppioni
authors.affiliation: Department of Medical Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Massari
authors.affiliation: Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giunchi
authors.affiliation: Laboratory of Oncologic Molecular Pathology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Altimari
authors.affiliation: Department of Medical Oncology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Ciccarese
authors.affiliation: Department of Urology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Bimbatti
authors.affiliation: Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.affiliation: Department of Medical Oncology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacovelli
authors.affiliation: Department of Medical Oncology, University of Pavia, Pavia, Italy.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Department of Pathology, University of Helsinki, Faculty of Medicine, Helsinki, Finland.
authors.forename: Sarhadi
authors.initials: S
authors.lastname: Virinder
authors.affiliation: Department of Medical Oncology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.affiliation: Department of Urology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Artibani
authors.affiliation: Department of Urology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Schiavina
authors.affiliation: Department of Medical Oncology, S.Orsola-Malpighi Hospital, Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ardizzoni
authors.affiliation: Department of Pathology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Pathology, University of Helsinki, Faculty of Medicine, Helsinki, Finland.
authors.forename: Sakari
authors.initials: S
authors.lastname: Knuutila
authors.affiliation: Department of Pathology, Diagnostics and Public Health University of Verona, Verona, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Martignoni
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007558:Italy; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors
keywords: Pathology Section; VHL; metastatic disease; next generation sequencing; renal cell carcinoma; target therapy