Wide spetcrum mutational analysis of metastatic renal cell cancer: a retrospective next generation sequencing approach.

Michelangelo Fiorentino,Matteo Brunelli,Sarhadi Virinder,Riccardo Schiavina,Aldo Scarpa,Andrea Ardizzoni,Walter Artibani,Francesca Giunchi,Roberto Iacovelli,Chiara Ciccarese,Elisa Gruppioni,Annalisa Altimari,Davide Bimbatti,Francesco Massari,Guido Martignoni,Sakari Knuutila,Camillo Porta,Giampaolo Tortora

doi:10.18632/oncotarget.12551

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.

Highlights

Renal cell carcinoma (RCC) accounts for the 2-3%of all adult malignancies, the seventh most common cancer in men and the ninth in women. [1] Localized RCC can be successfully cured by surgery in most cases
RCC histotypes were distributed as follows: 19 (86%) ccRCC and 4 (18%) papillary RCC
The ccRCC is largely the most common histotype and it is tightly associated with alteration of the VHL1-HIF pathway, while non-clear cell tumors are characterized by alterations of the PI3K and MET pathways

Summary

Introduction

Renal cell carcinoma (RCC) accounts for the 2-3%of all adult malignancies, the seventh most common cancer in men and the ninth in women. [1] Localized RCC can be successfully cured by surgery in most cases. No significant associations were found among RCC histotype, mutation variants and response to therapies. We identified mutations in the genes VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1 and TP53.

Results

Conclusion