Uniform genomic data analysis in the NCI Genomic Data Commons

Zhang, Zhenyu; Hernandez, Kyle M.; Savage, Jeremiah; Li, Shenglai; Miller, Dan; Agrawal, Stuti; Ortuño, Francisco; Staudt, Louis M.; Heath, Allison P.; Grossman, Robert L.

doi:10.1038/s41467-021-21254-9

Cited by 88 publications

(54 citation statements)

References 43 publications

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“…The discovery cohort included patients from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=149; 123 high-risk) (dbGAP accession ID phs000218.v22.p8) (online supplemental table 1). RNAseq paired-end (PE) FastQ files, whole exome sequencing (WES) alignment BAM files, somatic mutation MAF (Mutation Annotation Format) files, and clinical data were downloaded from Genomic Data Commons (GDC) 30 (https:// portal. gdc.…”

Section: Study Cohorts and Datasetsmentioning

confidence: 99%

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Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma

Bao

Spranger

Hernandez

et al. 2021

J Immunother Cancer

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BackgroundTumor-infiltrating CD8+ T cells and neoantigens are predictors of a favorable prognosis and response to immunotherapy with checkpoint inhibitors in many types of adult cancer, but little is known about their role in pediatric malignancies. Here, we analyzed the prognostic strength of T cell-inflamed gene expression and neoantigen load in high-risk neuroblastoma. We also compared transcriptional programs in T cell-inflamed and non-T cell-inflamed high-risk neuroblastomas to investigate possible mechanisms of immune exclusion.MethodsA defined T cell-inflamed gene expression signature was used to categorize high-risk neuroblastomas in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) program (n=123), and the Gabriella Miller Kids First (GMKF) program (n=48) into T cell-inflamed, non-T cell-inflamed, and intermediate groups. Associations between the T cell-inflamed and non-T cell-inflamed group, MYCN amplification, and survival were analyzed by Cox proportional hazards models. Additional survival analysis was conducted after integrating neoantigen load predicted from somatic mutations. Pathways activated in non-T cell-inflamed relative to T cell-inflamed tumors were analyzed using causal network analysis.ResultsPatients with T cell-inflamed high-risk tumors showed improved overall survival compared with those with non-T cell-inflamed tumors (p<0.05), independent of MYCN amplification status, in both TARGET and GMKF cohorts. Higher neoantigen load was also associated with better event-free and overall survival (p<0.005) and was independent of the T cell-inflamed signature. Activation of MYCN, ASCL1, SOX11, and KMT2A transcriptional programs was inversely correlated with the T cell-inflamed signature in both cohorts.ConclusionsOur results indicate that tumors from children with high-risk neuroblastoma harboring a strong T cell-inflamed signature have a more favorable clinical outcome, and neoantigen load is a prognosis predictor, independent of T cell inflammation. Strategies to target SOX11 and other signaling pathways associated with non-T cell-inflamed tumors should be pursued as potential immune-potentiating interventions.

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Section: Study Cohorts and Datasetsmentioning

confidence: 99%

“…For the discovery cohort, the somatic mutations were harmonized using four somatic variant callers (MuTect2, VarScan2, SomaticSniper, and MuSE). 30 After rigorous filtering following GDC's guidelines (https:// docs. gdc.…”

Section: Somatic Mutation Detection Hla Genotyping and Neoantigen Predictionmentioning

confidence: 99%

Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma

Bao

Spranger

Hernandez

et al. 2021

J Immunother Cancer

Self Cite

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“…It is now possible to compare miRNA levels between tumors and normal adjacent tissues on a large collection of human cases [Zhang et al, 2021], allowing a rigorous assessment of miR-34a expression in tumorigenesis. Selecting every cancer type where miRNA expression is available for primary tumor and normal adjacent tissue, in at least 10 studied cases (n=20 cancer types), we did not find any cancer type where miR-34a was significantly down-regulated (Figure 1 A ).…”

Section: Resultsmentioning

confidence: 99%

A rationalized definition of general tumor suppressor microRNAs excludes miR-34a

Mockly

Houbron

Seitz

2021

Preprint

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The miR-34a microRNA (miRNA) is currently thought to act as a tumor suppressor: its locus is frequently deleted in human tumors and it is believed to repress cell proliferation. We re-visited the evidence of its anti-cancer activity. Our results show that miR-34a is not generally down-regulated in primary tumors relatively to normal adjacent tissues, and the occasional deletion of miR-34a in human cancers is not due to an anti-tumorigenic activity of that gene, but rather, to its genomic proximity with an actual tumor suppressor. Its anti-proliferative action was observed upon large, supra-physiological transfection of synthetic miR-34a in cultured cells, and our data indicates that endogenous miR-34a levels do not have such an effect. We thus conclude that the generally accepted tumor-suppressive function of miR-34a is erroneous.

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“…The package contains the TCGA consortium-provided level 3 data, generated by the HiSeq and GenomeAnalyzer platforms, from 450 primary colorectal cancer patient samples [53]. For a more comprehensive and up-to-date phenotype information, associated patients' clinical data were retrieved from the genomic data commons [54][55][56][57].…”

Section: Biomedical Significance Experiments Datamentioning

confidence: 99%

A Knowledge-guided Mechanistic Model of Synthetic Lethality in the HCT116 Vorinostat-resistant Colon Cancer Xenograft Model Cell-line

Aiyetan

2021

Preprint

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With an overall lifetime risk of about 4.3% and 4.0%, in men and women respectively, colorectal cancer remains the third leading cause of cancer-related deaths in the United States. In persons aged 55 and below, its rate increased at 1% per year in the years 2008 to 2017 despite the steady decline associated with improved screening, early diagnosis and treatment in the general population. Besides standardized therapeutic regimen, many trials continue to evaluate the potential benefits of vorinostat, mostly in combination with other anti-neoplastic agents for its treatment. Vorinostat, an FDA approved anti-cancer drug known as suberoylanilide hydroxamic acid (SAHA), an histone deacylase (HDAC) inhibitor, through many mechanisms, causes cancer cell arrest and death. However, like many other anti-neoplastic agents, resistance and or failures have been observed. In the HCT116 colon cancer cell line xenograft model, exploiting potential lethal molecular interactions by additional gene knockouts restored vorinotat sensitivity. This phenomenon, known as synthetic lethality, offers a promise to selectively target cancer cells. Although without clearly delineated understanding of underlying molecular processes, it has been demonstrated as an effective cancer-killing mechanism. In this study, we aimed to elucidate mechanistic interactions in multiple perturbations of identified synthetically lethal experiments, particularly in the vorinostat-resistant HCT116 (colon cancer xenograft model) cell line. Given that previous studies showed that knocking down GLI1, a downstream transcription factor involved in the Sonic Hedgehog pathway -- an embryonal gene regulatory process, resulted in restoration of vorinostat sensitivity in the HCT116 colorectal cancer cell line, we hypothesized that vorinostat resistance is a result of upregulation of embryonal cellular differentiation processes; we hypothesized that elucidated regulatory mechanism would include crosstalks that regulate this biological process. We employed a knowledege-guided fuzzy logic regulatory inference method to elucidate mechanistic relationships. We validated inferred regulatory models in independent datasets. In addition, we evaluated the biomedical significance of key regulatory network genes in an independent clinically annotated dataset. We found no significant evidence that vorinostat resistance is due to an upregulation of embryonal gene regulatory pathways. Our observation rather support a topological rewiring of canonical oncogenic pathways around the PIK3CS, AKT, RAS/BRAF etc. regulatory pathways. Reasoning that significant regulatory network genes are likely implicated in the clinical course of colorectal cancer, we show that the identified key regulatory network genes' expression profile are able to predict short- to medium-term survival in colorectal cancer patients -- providing a rationale basis for prognostification and potentially effective combination of therapeutics that target these genes along with vorinostat in the treatment of colorectal cancer.

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Uniform genomic data analysis in the NCI Genomic Data Commons

Cited by 88 publications

References 43 publications

Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma

Immunogenomic determinants of tumor microenvironment correlate with superior survival in high-risk neuroblastoma

A rationalized definition of general tumor suppressor microRNAs excludes miR-34a

A Knowledge-guided Mechanistic Model of Synthetic Lethality in the HCT116 Vorinostat-resistant Colon Cancer Xenograft Model Cell-line

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