Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

Gao, Jianjiong; Aksoy, Bülent Arman; Doğrusöz, Uğur; Dresdner, Gideon; Groß, Benjamin; Sumer, S. Onur; Sun, Yichao; Jacobsen, Anders; Sinha, Rileen; Larsson, Erik; Cerami, Ethan; Sander, Chris; Schultz, Nikolaus

doi:10.1126/scisignal.2004088

Cited by 12,588 publications

(12,257 citation statements)

References 34 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%

“…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. 55 Copy number levels were generated on the Affymetrix SNP Array 6.0 and normalized using the supervised normalization of microarrays (SNM) framework 56 as described by 55 and also using DNAcopy 54,57 to define low- and high-level copy number thresholds. A 173-gene exome sequencing panel was used to identify somatic gene mutations and generate measures of mutational burden (gene count).…”

Section: Methodsmentioning

confidence: 99%

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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%

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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“…Variants were then compared with the following public databases; the Single Nucleotide Polymorphism database (dbSNP) together with 1000 Genomes (Abecasis et al, 2012), the National Heart, Lung and Blood Institute (NHLBI) Exome Sequencing Project (ESP6500) (http://evs.gs.washington.edu/EVS/), and the Exome Aggregation Consortium (ExAC), Cambridge, MA (URL:http://exac.broadinstitute.org). Selected variants with a MAF <1% were also compared with cbioportal (http://www.cbioportal.org/) (Cerami et al, 2012; Gao et al, 2013) and the COSMIC database (Forbes et al, 2015). To distinguish variants from local polymorphisms between 200 and 248 anonymized in‐house normal control blood samples were sequenced over the positions of interest.…”

Section: Methodsmentioning

confidence: 99%

GREM1 and POLE variants in hereditary colorectal cancer syndromes

Rohlin

Eiengård

Lundstam

et al. 2015

Genes Chromosomes & Cancer

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Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high‐penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy‐number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease‐causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease‐causing mutations in hereditary CRC syndromes. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal

Cited by 12,588 publications

References 34 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

GREM1 and POLE variants in hereditary colorectal cancer syndromes

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