Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis. RESULTS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH). CONCLUSIONS: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).
Source: New England Journal of Medicine
Author: The Cancer Genome Atlas Research Network
Institution: National Institutes of Health
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: Enhancing Translational Science via Prospective Investigation, Large Scale Sequencing and Analysis of Genomes, The USC-JHU Cancer Epigenome Characterization Center, A Platform for Large-Scale Genomic Discovery, The BCM Tumor Genome Characterization Center, MSKCC Center for Translational Cancer Genomic Analysis, UCSC-Buck Inst. Genome Data Analysis Center for TCGA Research Network (GDAC), The Human Genome Sequencing Center, Harvard Genome Characterization Center, Cancer transcriptome characterization using massively parallel DNA sequencing, Next-Generation Clustered Heat Maps for fluent, interactive exploration of omic data, University of Pittsburgh Clinical and Translational Science Institute, Integrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC), The Cancer Genome Atlas Data Analysis Center, Cloud Based Resource for Data Hosting, Visualization and Analysis Using UCSC Canc, Genome Characterization Center (GCC), Inhibiting VHL-positive kidney cancer, Gene Expression Patterns in Human Tumors Identified Using Transcript Sequencing, TCGA Data Analysis Center at Berkeley, Center for Systems Analysis of the Cancer Regulome, Cancer Center Support Grant, Mayo Clinic Comprehensive Cancer Center Support Grant, Cancer Center Support Grant, Roswell Park Cancer Center Support Grant, Cancer Center Support Grant
OpenAlex ID: W2111867681