Comprehensive Genomic Analysis of Metastatic Non-Clear-Cell Renal Cell Carcinoma to Identify Therapeutic Targets.

Non-clear-cell renal cell carcinoma (nccRCC) encompasses approximately 20% of renal cell carcinomas and includes subtypes that vary in clinical and molecular biology. Compared with clear cell renal cell carcinoma, nccRCC demonstrates limited sensitivity to conventional vascular endothelial growth factor- and mammalian target of rapamycin-directed agents, indicating a need for better therapies. Characterizing the genomic landscape of metastatic nccRCC variants may help define novel therapeutic strategies. We retrospectively analyzed tumor tissue from patients with metastatic nccRCC who consented to genomic analysis of their tumor and germline DNA. A hybridization capture-based assay was used to identify single nucleotide variants and small insertions and deletions across more than 340 cancer-associated genes with germline comparison. Clinical actionability of somatic mutations was assessed using OncoKB levels of evidence. Microsatellite instability (MSI) in the tumor was investigated. Of 116 patients included in the analysis, 57 (49%) presented with de novo metastatic disease, and 59 (51%) presented with localized disease that later metastasized. Subtype classifications included unclassified (n = 41; 35%), papillary (n = 26; 22%), chromophobe (n = 17; 15%), translocation associated (n = 13; 11%), and other (n = 19; 16%). Of all tumors, 15 (13%) had putative driver somatic alterations amenable to targeted therapies, including alterations in The mutation profiles of metastatic nccRCC vary by subtype. Comprehensive analysis of somatic mutations, germline mutations, and MSI, interpreted via an annotated precision oncology knowledge base, identified potentially targetable alterations in 22% of patients, which merits additional investigation.

Informations de copyright

© 2019 by American Society of Clinical Oncology.

Déclaration de conflit d'intérêts

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Maria I. CarloConsulting or Advisory Role: PfizerDavid M. HymanConsulting or Advisory Role: Atara Biotherapeutics, Chugai Pharma, CytomX Therapeutics, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, Genentech Research Funding: AstraZeneca, Puma Biotechnology, Loxo Travel, Accommodations, Expenses: Genentech, Chugai PharmaMarc LadanyiHonoraria: Merck (I) Consulting or Advisory Role: National Comprehensive Cancer Network/AstraZeneca Tagrisso RFP Advisory Committee, Takeda, Bristol-Myers Squibb, Bayer, Merck (I) Research Funding: Loxo (Inst), Helsinn TherapeuticsMark RobsonHonoraria: AstraZeneca, Pfizer Consulting or Advisory Role: McKesson, AstraZeneca, Merck Research Funding: AstraZeneca (Inst), Myriad Genetics (Inst), InVitae (Inst), Pfizer (Inst), Abbvie (Inst), Tesaro (Inst), Medivation (Inst) Travel, Accommodations, Expenses: AstraZenecaChung-Han LeeConsulting or Advisory Role: Exelixis, Eisai Research Funding: Pfizer (Inst), Eisai (Inst), Bristol-Myers Squibb (Inst), Calithera Biosciences (Inst), Exelixis (Inst) Travel, Accommodations, Expenses: EisaiDarren R. FeldmanResearch Funding: Novartis, Seattle Genetics, Decibel Therapeutics (Inst) Other Relationship: UpToDateRobert J. MotzerConsulting or Advisory Role: Pfizer, Novartis, Eisai, Exelixis, Merck, Genentech, Incyte Research Funding: Pfizer (Inst), Bristol-Myers Squibb (Inst), Eisai (Inst), Novartis (Inst), Genentech (Inst)Martin H. VossHonoraria: Novartis Consulting or Advisory Role: Novartis, Calithera Biosciences, GlaxoSmithKline, Exelixis, Pfizer, Alexion Pharmaceuticals, Eisai, Corvus Pharmaceuticals Research Funding: Bristol-Myers Squibb, Genentech Travel, Accommodations, Expenses: Takeda, MedImmune, Eisai No other potential conflicts of interest were reported.