Cancer Vulnerabilities Unveiled by Genomic Loss

Nijhawan, Deepak; Zack, Travis I.; Ren, Yin; Strickland, Matthew R.; Lamothe, Rebecca; Schumacher, Steven E.; Tsherniak, Aviad; Besche, Henrike C.; Rosenbluh, Joseph; Shehata, Shyemaa; Cowley, Glenn S.; Weir, Barbara A.; Goldberg, Alfred L.; Mesirov, Jill P.; Root, David E.; Bhatia, Sangeeta N.; Beroukhim, Rameen; Hahn, William C.

doi:10.1016/j.cell.2012.07.023

Cited by 212 publications

(248 citation statements)

References 35 publications

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“…PIK3CA is an example of oncogene addiction (29), including when it is not mutated (30), and thus could be considered as a primary target for therapy. Both PIK3CA expression and the somatic mutations in its pathway (PIK3CA/AKT1/PTEN axis) were retained in the final multivariate model, proving to be important and independent cofactors in prognosis.…”

Section: Discussionmentioning

confidence: 99%

Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer

Volinia

Croce

2013

Proc. Natl. Acad. Sci. U.S.A.

138

107

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The optimal management of breast cancer (BC) presents challenges due to the heterogeneous molecular classification of the disease. We performed survival analysis on a cohort of 466 patients with primary invasive ductal carcinoma (IDC), the most frequent type of BC, by integrating mRNA, microRNA (miRNA), and DNA methylation next-generation sequencing data from The Cancer Genome Atlas (TCGA). Expression data from eight other BC cohorts were used for validation. The prognostic value of the resulting miRNA/mRNA signature was compared with that of other prognostic BC signatures. Thirty mRNAs and seven miRNAs were associated with overall survival across different clinical and molecular subclasses of a 466-patient IDC cohort from TCGA. The prognostic RNAs included PIK3CA, one of the two most frequently mutated genes in IDC, and miRNAs such as hsa-miR-328, hsa-miR-484, and hsa-miR-874. The area under the curve of the receiver-operator characteristic for the IDC risk predictor in the TCGA cohort was 0.74 at 60 mo of overall survival (P < 0.001). Most relevant for clinical application, the integrated signature had the highest prognostic value in early stage I and II tumors (receiver-operator characteristic area under the curve = 0.77, P value < 0.001). The genes in the RNA risk predictor had an independent prognostic value compared with the clinical covariates, as shown by multivariate analysis. The integrated RNA signature was successfully validated on eight BC cohorts, comprising a total of 2,399 patients, and it had superior performance for risk stratification with respect to other RNA predictors, including the mRNAs used in MammaPrint and Oncotype DX assays.genomics | prognosis | ncRNA | mutation

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Section: Discussionmentioning

confidence: 99%

Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer

Volinia

Croce

2013

Proc. Natl. Acad. Sci. U.S.A.

138

107

View full text Add to dashboard Cite

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“…A genomics approach termed CYCLOPS identified singlecopy deletions of PSMC2, a component of the proteasome, as a recurrent event in a subset of HGSOC (32). Both hemizygous PSMC2 copy number loss and transcriptional repression of UBB might serve to optimize cell fitness by tuning protein fate in a way that stabilizes prosurvival proteins during tumorigenesis (33 To restrict the analysis to the human cells in the sample, results were normalized to human GAPDH by the ΔΔCT method.…”

Section: Discussionmentioning

confidence: 99%

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Kedves¹,

Gleim²,

Liang³

et al. 2017

Journal of Clinical Investigation

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“…Rewiring of the transcriptome can result from either genomic aberrations or epigenomic changes. Many chromosomal regions are recurrently lost in cancers, and some of these regions harbor genes that encode 19S proteasome subunits, such as PSMC2 (26). DNA sequencing data from the CCLE resource enabled us to determine whether the differential reduction in 19S subunit mRNA expression was associated with copy-number loss.…”

Section: Mechanisms That Reduce Expression Of Specific 19s Proteasomementioning

confidence: 99%

Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers

Tsvetkov

Sokol

Jin

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The use of proteasome inhibitors to target cancer’s dependence on altered protein homeostasis has been greatly limited by intrinsic and acquired resistance. Analyzing data from thousands of cancer lines and tumors, we find that those with suppressed expression of one or more 19S proteasome subunits show intrinsic proteasome inhibitor resistance. Moreover, such proteasome subunit suppression is associated with poor outcome in myeloma patients, where proteasome inhibitors are a mainstay of treatment. Beyond conferring resistance to proteasome inhibitors, proteasome subunit suppression also serves as a sentinel of a more global remodeling of the transcriptome. This remodeling produces a distinct gene signature and new vulnerabilities to the proapoptotic drug, ABT-263. This frequent, naturally arising imbalance in 19S regulatory complex composition is achieved through a variety of mechanisms, including DNA methylation, and marks the emergence of a heritably altered and therapeutically relevant state in diverse cancers.

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Cancer Vulnerabilities Unveiled by Genomic Loss

Cited by 212 publications

References 35 publications

Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer

Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers

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