The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Ricketts, Christopher J.; Cubas, Aguirre A. de; Fan, Huihui; Smith, Christof C.; Lang, Martin; Reznik, Ed; Bowlby, Reanne; Gibb, Ewan A.; Akbani, Rehan; Beroukhim, Rameen; Bottaro, Donald P.; Choueiri, Toni K.; Gibbs, Richard A.; Godwin, Andrew K.; Haake, Scott M.; Hakimi, A. Ari; Henske, Elizabeth P.; Hsieh, James J.; Ho, Thai H.; Kanchi, Rupa S.; Krishnan, Bhavani; Kwiatkowski, David J.; Lui, Wembin; Merino, María J.; Mills, Gordon B.; Myers, Jerome; Nickerson, Michael L.; Reuter, Victor E.; Schmidt, Laura S.; Shelley, Carl Simon; Shen, Hui; Shuch, Brian; Signoretti, Sabina; Srinivasan, Ramaprasad; Tamboli, Pheroze; Thomas, George V.; Vincent, Benjamin G.; Vocke, Cathy D.; Wheeler, David A.; Yang, Lixing; Kim, William Y.; Roberts, Lewis R.; Spellman, Paul T.; Rathmell, W. Kimryn; Linehan, W. Marston

doi:10.1016/j.celrep.2018.06.032

Cited by 478 publications

(372 citation statements)

References 61 publications

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“…Further study is required to assess this possibility. However, homozygous mutations in TSC1 are seen in ∼8% of bladder cancer (Robertson et al, 2017) and in TSC1 or TSC2 in ∼50% of perivascular epithelioid cell neoplasms (Dickson et al, 2013), and activating mutations in MTOR are seen in ∼5% of clear cell renal cell carcinoma (Ricketts et al, 2018). Furthermore, our TSC1-deficient bladder cancer cell line xenograft model showed a sustained and complete response to THZ1 treatment ( Fig.…”

Section: Discussionmentioning

confidence: 73%

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Zarei

Nassar

et al. 2019

Journal of Experimental Medicine

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Tuberous sclerosis complex (TSC) is characterized by tumor development in the brain, heart, kidney, and lungs. In TSC tumors, loss of the TSC1/TSC2 protein complex leads to activation of mTORC1 with downstream effects on anabolism and cell growth. Because mTORC1 activation enhances mRNA transcription, we hypothesized that aberrant mTORC1 activation might confer TSC-null cell dependence on transcriptional regulation. We demonstrate that TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. Mechanistic studies revealed that CDK7 inhibition markedly reduces glutathione levels and increases reactive oxygen species due to reduced expression of NRF2 and glutathione biosynthesis genes. Treatment of both Tsc2+/− mice and a TSC1-null bladder cancer xenograft model with a CDK7 inhibitor showed marked reduction in tumor volume and absence of regrowth in the xenograft model. These results suggest that CDK7 inhibition is a promising therapeutic approach for treatment of TSC-associated tumors and cancers with mutations in either TSC1 or TSC2.

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Section: Discussionmentioning

confidence: 73%

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Zarei

Nassar

et al. 2019

Journal of Experimental Medicine

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“…The gene expression quantification files (HTSeq‐Counts and HTSeq‐FPKM), somatic copy number alteration (SCNA) segment files (SEG), mutation annotation files (MAF) and slide images of ccRCC were downloaded from the TCGA repository. Because the original KIRC contains misdiagnosed cases, we used the cohort of the latest pan‐RCC TCGA publication 4 that has excluded the cases with inconsistent diagnosis. After carefully reviewing the histology and expression profile of all cases, we further identified two misclassified cases.…”

Section: Methodsmentioning

confidence: 99%

Differential expression analysis of clear cell renal cell carcinomas in The Cancer Genome Atlas distinguishes an aggressive subset enriched with chromosomes 7 and 12 gains

Pan¹,

Yeh

Wang³

et al. 2020

Histopathology

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Aims The Cancer Genome Atlas (TCGA) provides an integrated resource for investigating the genetic, phenotypical and clinical characteristics of cancer. In this study, we aimed to define distinct subsets of clear cell renal cell carcinoma (ccRCC) through differential expression and principal component analyses. Methods and results We used DESeq2 to examine the expression profiles of 472 cases in TCGA. After a process of segregation and regrouping, we compared the mutation and copy number variation landscapes to discern two major clusters: cluster 1, composed mainly of classic ccRCC, and cluster 2, which was associated with gains at chromosomes 7 and 12. Gene set enrichment analysis disclosed that cluster 2 tumours were enriched in genes involving epithelial–mesenchymal transition. Histologically, cluster 2 tumours frequently exhibited cell elongation or spindling. Patients with cluster 2 tumours or tumours harbouring chromosomes 7 or 12 gains had a significantly greater cumulative incidence of mortality. We then employed fluorescence in‐situ hybridisation with probes against chromosomes 7 and 12 in a cohort of 119 cases of ccRCC from our institute for validation. Chromosomes 7 and 12 gains were associated with lower survival rates in both univariate and multivariate analyses. Conclusions Our study demonstrates that genetic data obtained through appropriate molecular methodologies can be a useful adjunct to help predict prognosis. It also provides an example of exploring TCGA to extract meaningful information that can eventually contribute to precision medicine.

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“…12 In addition, SCNA types that were used in the present study are different from those of previous comprehensive analyses. 12,41,42 However, a correlation of a specific SCNA with patient prognosis, including disease-free survival, was not observed in a "big data" cohort study (comparison of the present study with other big data studies, including TCGA 41 and "Integrated Molecular Analysis of Clear-cell Renal Cell Carcinoma," 42 as summarized in Supporting Information Table). In the present study, irrespective of small studies, we showed that the 3p24.3 mixed type is correlated with diseasefree survival, a finding that is supported by the validation cohort in which disease-free survival was correlated with a favorable prognosis.…”

Section: Differences In the Scna Patterns Between Subgroups 1 And 2mentioning

confidence: 95%

“…9,10 Several studies have demonstrated that the presence of multiple SCNAs is associated with overall patient survival, tumor stage, and development of metastasis. 11,12 Genome-wide assessment using somatic SCNAs provides useful information for identifying overall genomic profiles of cancer cells. 11,12 The accumulation of SCNAs contributes to tumor heterogeneity and consequently striking differences in the presence of SCNAs between primary and metastatic sites.…”

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confidence: 99%

“…11,12 Genome-wide assessment using somatic SCNAs provides useful information for identifying overall genomic profiles of cancer cells. 11,12 The accumulation of SCNAs contributes to tumor heterogeneity and consequently striking differences in the presence of SCNAs between primary and metastatic sites. 13 The accumulation of SCNAs plays important roles in tumor progression in RCC as well as other types of cancer.…”

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confidence: 99%

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Comprehensive analysis of somatic copy number alterations in clear cell renal cell carcinoma

Tsuyukubo

Ishida

Osakabe

et al. 2020

Molecular Carcinogenesis

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Somatic copy number alterations (SCNAs) are important biological characteristics that can identify genome‐wide alterations in renal cell carcinoma (RCC). Recent studies have shown that SCNAs have potential value for determining the prognosis of RCC. We examined SCNAs using the Affymetrix platform to analyze samples from 59 patients with clear cell RCCs (ccRCCs) including first cohort (30 cases) and second cohort (validation cohort, 29 cases). We stratified SCNAs in the ccRCCs using a hierarchical cluster analysis based on SCNA types, including gain, loss of heterozygosity (LOH), copy neutral LOH, mosaic, and mixed types. In this way, the examined two cohorts were categorized into two subgroups (1 and 2). Although the frequency of mixed type was higher in subgroup 1 than in subgroup 2 in the two cohorts, the association did not reach statistical significance. There was a significant difference in the frequency of metachronous metastasis between subgroups 1 and 2 (subgroup 2 > 1). In addition, subgroup 2 was retained in multivariate analysis of both cohorts. We examined whether there were specific alleles differing between subgroups 1 and 2 in both cohorts. We found that there was indeed a statistically significant difference in the 3p mixed types. Among the 3p mixed type, we found that 3p24.3 mixed type was inversely correlated with the presence of metachronous metastasis in ccRCC. The association was also retained in multivariate analysis in second cohort. We suggest that the 3p24.3 mixed type may be a novel marker to predict a favorable prognosis in ccRCC.

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The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Abstract: In the originally published version of this article, the author list contained two errors. Specifically, David J. Kwiatkowski was misspelled as David J. Kwaitkowski, and William Y. Kim was inadvertently written as William T. Kim. Both names have been corrected online.

Cited by 478 publications

References 61 publications

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion

Differential expression analysis of clear cell renal cell carcinomas in The Cancer Genome Atlas distinguishes an aggressive subset enriched with chromosomes 7 and 12 gains

Comprehensive analysis of somatic copy number alterations in clear cell renal cell carcinoma

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