The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

Cerami, Ethan; Gao, Jianjiong; Doğrusöz, Uğur; Groß, Benjamin; Sumer, S. Onur; Aksoy, Bülent Arman; Jacobsen, Anders; Byrne, Caitlin J.; Heuer, Michael; Larsson, Erik; Antipin, Yevgeniy; Reva, Boris; Goldberg, Arthur P.; Sander, Chris; Schultz, Nikolaus

doi:10.1158/2159-8290.cd-12-0095

Cited by 13,997 publications

(13,588 citation statements)

References 15 publications

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“…52 GISTIC-processed copy number data were obtained from cBioPortal (http://www.cbioportal.org/). 53,54 In aggregate, 1,895 evaluable cases had corresponding gene expression, mutation count and overall survival data. Gene expression profiles were generated using the Illumina_Human_WG-v3 array platform 24 and normalized by quantile normalization with linear modeling batch correction, as described elsewhere.…”

Section: Methodsmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Methodsmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…The cBioPortal (Cerami et al ., 2012; Gao et al ., 2013) (http://www.cbioportal.org/index.do) database contains the most well‐organized and comprehensive data on cancer genetics for various cancer types. The TCGA Provisional datasets for individual cancer types cover genetic abnormalities, transcriptomes determined by either cDNA microarray or RNA sequencing, and the detailed clinical characteristics including disease outcomes (recurrence and mortality).…”

Section: Methodsmentioning

confidence: 99%

“…The largest TCGA Provisional dataset within the cBioPortal database (Cerami et al ., 2012; Gao et al ., 2013) (http://www.cbioportal.org/index.do), which includes 492 patients with follow‐up data, was used to derive 696 DEGs that are associated with the 9‐gene signature of the MUC1 genomic network (Lin et al ., 2017). These DEGs were defined at q < 0.001.…”

Section: Methodsmentioning

confidence: 99%

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

Jiang

Mei

et al. 2018

Molecular Oncology

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We report here numerous novel genes and multiple new signatures which robustly predict prostate cancer (PC) recurrence. We extracted 696 differentially expressed genes relative to a reported PC signature from the TCGA dataset (n = 492) and built a 15‐gene signature (SigMuc1NW) using Elastic‐net with 10‐fold cross‐validation through analyzing their expressions at 1.5 standard deviation/SD below and 2 SD above a population mean. SigMuc1NW predicts biochemical recurrence (BCR) following surgery with 56.4% sensitivity, 72.6% specificity, and 63.24 median months disease free (MMDF) (P = 1.12e‐12). The prediction accuracy is improved with the use of SigMuc1NW's cutpoint (P = 3e‐15) and is further enhanced (sensitivity 67%, specificity 75.7%, MMDF 45.2, P = 0) when all 15 genes were analyzed through their cutpoints instead of their SDs. These genes individually associate with BCR using either SD or cutpoint as the cutoff points. Eight of 15 genes are individual risk factors after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. Eleven of 15 genes are novel to PC. SigMuc1NW discriminates BCR with time‐dependent AUC (tAUC) values of 76.6% at 11.5 months (76.6%–11.5 m), 73.8%‐22.3 m, 78.5%‐32.1 m, and 76.4%–48.4 m. SigMuc1NW is correlated with adverse features of PC, high Gleason scores (odds ratio/OR 1.48, P < 2e‐16), and advanced tumor stages (OR 1.33, P = 4.37e‐13). SigMuc1NW remains an independent risk factor of BCR (HR 2.44, 95% CI 1.53–3.87, P = 1.62e‐4) after adjusting for age at diagnosis, Gleason score, surgical margin, and tumor stage. In an independent PC (MSKCC) cohort (n = 140), these 15 genes were altered in PC vs normal tissue, metastatic PCs vs primary PCs, and recurrent PCs vs nonrecurrent PCs. Importantly, a 10‐gene subsignature SigMuc1NW1 predicts BCR in MSKCC (P = 3.11e‐15) and TCGA (P = 3.13e‐12); SigMuc1NW1 discriminates BCR at 18.4 m with tAUC as 82.5%. Collectively, our analyses support SigMuc1NW as a novel and robust signature in predicting BCR of PC.

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“…The Drosophila melanogaster homolog of SPOP, Roadkill/HIB, is essential for early development (Kent et al , 2006). Recent efforts to sequence the cancer genome have identified many mutations in SPOP that are associated with cancers (Lawrence et al , 2014), notably prostate (Kim et al , 2013), breast (Kim et al , 2011), endometrial (Le Gallo et al , 2012), and gastric (Kim et al , 2013) cancers [Appendix Fig S1 and www.cbioportal.org (Cerami et al , 2012; Gao et al , 2013)]. SPOP contains three domains; it recruits substrates through its MATH ( m eprin a nd t raf h omology) domain (Zhuang et al , 2009), forms dimers through its BTB ( b ric à brac, t ramtrack, b road complex) domain (Zhuang et al , 2009; Errington et al , 2012), and forms either dimers or tetramers through its BACK ( B TB a nd C ‐terminal K elch) domain (Errington et al , 2012; van Geersdaele et al , 2013 and Fig 1A).…”

Section: Introductionmentioning

confidence: 99%

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

et al. 2016

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Membrane‐less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher‐order assemblies influences the recruitment of the speckle‐type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin‐3‐RING ubiquitin ligase (CRL3) substrate adaptor, self‐associates into higher‐order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild‐type SPOP localizes to liquid nuclear speckles, self‐association‐deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB‐mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration‐dependent populations of the resulting oligomeric species. Higher‐order oligomerization of SPOP stimulates CRL3SPOP ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher‐order protein self‐association may be a general mechanism to concentrate functional components in membrane‐less cellular bodies.

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The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data

Cited by 13,997 publications

References 15 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Construction of a set of novel and robust gene expression signatures predicting prostate cancer recurrence

Higher‐order oligomerization promotes localization of SPOP to liquid nuclear speckles

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