Dataset Information

Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression.

ABSTRACT:

Purpose

Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing.

Experimental design

Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center (MSK)-IMPACT]; a subset was profiled using exome-sequencing and combined with exome data from The Cancer Genome Atlas (TCGA) for analysis. The prognostic value of specific somatic aberrations, tumor mutation burden (TMB), and fraction of copy-number-altered genome (FCNAg) was explored. In TCGA cases, neoantigen prediction and immune cell deconvolution were performed using RNA-sequencing and exome data. Overall survival estimates were computed using the Kaplan-Meier method; time-on-treatment was calculated for 14 MSK-IMPACT patients who underwent systemic therapy. Associations between molecular features and outcomes were evaluated using nonparametric testing.

Results

Copy-number aberrant tRCCs were associated with poor overall survival (P = 0.03). Pediatric patients had tumors with lower FCNAg (P = 0.01). In one adult case with two chronologically distinct tumor samples sequenced, we confirmed that copy-number events occurred early during evolution. TERT promoter mutations were found exclusively in high-stage tumors. We found that tRCCs displayed distinct angiogenesis and PD-L1 gene expression profiles compared with other RCC subtypes.

Conclusions

Tumors molecularly defined by increased copy-number variations were associated with aggressive disease in tRCC. A higher burden of genomic events in adults compared with pediatric cases likely reflects a more aggressive clinical course. The unique immunophenotypic characteristics of tRCC merit further exploration.

SUBMITTER: Marcon J

PROVIDER: S-EPMC7367714 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Publications

Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression.

Marcon Julian J DiNatale Renzo G RG Sanchez Alejandro A Kotecha Ritesh R RR Gupta Sounak S Kuo Fengshen F Makarov Vladimir V Sandhu Amar A Mano Roy R Silagy Andrew W AW Blum Kyle A KA Nassau Daniel E DE Benfante Nicole E NE Ortiz Michael V MV Carlo Maria I MI Chan Timothy A TA Motzer Robert J RJ Voss Martin H MH Coleman Jonathan J Russo Paul P Reuter Victor V Hakimi A Ari AA Reznik Ed E

Clinical cancer research : an official journal of the American Association for Cancer Research 20200327 14

<h4>Purpose</h4>Translocation renal cell carcinoma (tRCC) is a rare, aggressive renal cell carcinoma (RCC) subtype. There is currently limited understanding on the role of molecular alterations in the pathogenesis and progression of these tumors. We investigated the association between somatic alterations and clinical outcomes in two independent cohorts profiled using DNA sequencing.<h4>Experimental design</h4>Twenty-two tRCCs underwent targeted sequencing [Memorial Sloan Kettering Cancer Center ...[more]

PMID: 32220885

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Project description:Copy number variations (CNV) include net gains or losses of part or whole chromosomal regions. They differ from copy neutral loss of heterozygosity (cn-LOH) events which do not induce any net change in the copy number and are often associated with uniparental disomy. These phenomena have long been reported to be associated with diseases and particularly in cancer. Losses/gains of genomic regions are often correlated with lower/higher gene expression. On the other hand, loss of heterozygosity (LOH) and cn-LOH are common events in cancer and may be associated with the loss of a functional tumor suppressor gene. Therefore, identifying recurrent CNV and cn-LOH events can be important as they may highlight common biological components and give insights into the development or mechanisms of a disease. However, no currently available tools allow a comprehensive whole-genome visualization of recurrent CNVs and cn-LOH in groups of samples providing absolute quantification of the aberrations leading to the loss of potentially important information.To overcome these limitations, we developed aCNViewer (Absolute CNV Viewer), a visualization tool for absolute CNVs and cn-LOH across a group of samples. aCNViewer proposes three graphical representations: dendrograms, bi-dimensional heatmaps showing chromosomal regions sharing similar abnormality patterns, and quantitative stacked histograms facilitating the identification of recurrent absolute CNVs and cn-LOH. We illustrated aCNViewer using publically available hepatocellular carcinomas (HCCs) Affymetrix SNP Array data (Fig 1A). Regions 1q and 8q present a similar percentage of total gains but significantly different copy number gain categories (p-value of 0.0103 with a Fisher exact test), validated by another cohort of HCCs (p-value of 5.6e-7) (Fig 2B).aCNViewer is implemented in python and R and is available with a GNU GPLv3 license on GitHub https://github.com/FJD-CEPH/aCNViewer and Docker https://hub.docker.com/r/fjdceph/acnviewer/.aCNViewer@cephb.fr.

Dataset Information

Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression.

Purpose

Experimental design

Results

Conclusions

Publications

Comprehensive Genomic Analysis of Translocation Renal Cell Carcinoma Reveals Copy-Number Variations as Drivers of Disease Progression.

Similar Datasets

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