Dataset Information

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

ABSTRACT: On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifier genes were present within a specific subtype and spanned multiple subtypes. Differences in patient survival and in alteration of specific pathways (including hypoxia, metabolism, MAP kinase, NRF2-ARE, Hippo, immune checkpoint, and PI3K/AKT/mTOR) could further distinguish the subtypes. Immune checkpoint markers and molecular signatures of T cell infiltrates were both highest in the subtype associated with aggressive clear cell RCC. Differences between the genomic subtypes suggest that therapeutic strategies could be tailored to each RCC disease subset.

SUBMITTER: Chen F

PROVIDER: S-EPMC4794376 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

Chen Fengju F Zhang Yiqun Y Şenbabaoğlu Yasin Y Ciriello Giovanni G Yang Lixing L Reznik Ed E Shuch Brian B Micevic Goran G De Velasco Guillermo G Shinbrot Eve E Noble Michael S MS Lu Yiling Y Covington Kyle R KR Xi Liu L Drummond Jennifer A JA Muzny Donna D Kang Hyojin H Lee Junehawk J Tamboli Pheroze P Reuter Victor V Shelley Carl Simon CS Kaipparettu Benny A BA Bottaro Donald P DP Godwin Andrew K AK Gibbs Richard A RA Getz Gad G Kucherlapati Raju R Park Peter J PJ Sander Chris C Henske Elizabeth P EP Zhou Jane H JH Kwiatkowski David J DJ Ho Thai H TH Choueiri Toni K TK Hsieh James J JJ Akbani Rehan R Mills Gordon B GB Hakimi A Ari AA Wheeler David A DA Creighton Chad J CJ

Cell reports 20160303 10

On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron was one major determinant in the classification, reflecting differences among clear cell, chromophobe, and papillary RCC. Widespread molecular changes associated with TFE3 gene fusion or chromatin modifi ...[more]

PMID: 26947078

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Project description:Even though urothelial cancer (UC) is the fourth common tumor type among males, progress in treatment development has been deficient. Pathological assessment provides the urologists with only a broad classification, complicated by frequent disagreement among pathologist and the co-existence of different grading systems. Consequently, there is a great need for an objective, reproducible and biologically relevant classification system to make treatment more efficient. In the present investigation we present a molecular taxonomy for UC stratification based on integrated genomics. We used gene expression profiles from 308 UC to define seven molecular subtypes using step-by-step partitions and a bootstrap approach. Results were validated in three independent and publically available data sets. The subtypes differ significantly with respect to expression of cell cycle genes, of receptor tyrosine kinases particularity FGFR3, ERBB2 (HER2), and EGFR, of an FGFR3 associated gene expression signature, of cytokaratins, and of cell adhesion genes. The subtypes also differ significantly with respect to FGFR3, PIK3CA, and TP53 mutations. The expression of key proteins was validated by IHC on TMA. A further inspection indicated that the subtypes could be reduced to four major types of UC; Urobasal/D-driven, Genomically unstable/E-driven, Evolved urobasal, and Basal/SCC like, with characteristic and highly divergent molecular phenotypes. We show that the molecular subtypes cut across pathological classification and that tumors classified as one subtype maintain their characteristic molecular phenotype irrespective of pathological stage and grade. Available data from the Drugbank database and the Cochrane central registry of controlled trials indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathological classification. The presented molecular taxonomy stratifies UC into subtypes with distinct molecular phenotypes and biological properties. We anticipate that the molecular taxonomy will be a useful tool in future clinical investigations. Total RNA from fresh-frozen resection samples of 308 urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu). Supplementary files: GSE32894_non-normalized_308UCsamples.txt file = Raw intensity values for 308 UC (urothelial tumor) samples subjected only to background correction. GSE32894_reps_normals_preprocess*.txt files = Descriptive details and non-normalized data for technical replicates and normal samples that were used only in the preprocessing of the data. This dataset partly overlaps with Series GSE32549. Names of the overlapping sample names are the same, but the title of each sample is unique to the hybridization.

Dataset Information

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

Publications

Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.

Similar Datasets

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