An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review

[EN] Purpose: To systematically review evidence regarding the association of multi-parametric biomarkers with clinical outcomes and their capacity to explain relevant subcompartments of gliomas. Materials and Methods: Scopus database was searched for original journal papers from January 1st, 2007 to February 20th , 2017 according to PRISMA. Four hundred forty-nine abstracts of papers were reviewed and scored independently by two out of six authors. Based on those papers we analyzed associations between biomarkers, subcompartments within the tumor lesion, and clinical outcomes. From all the articles analyzed, the twenty-seven papers with the highest scores were highlighted to represent the evidence about MR imaging biomarkers associated with clinical outcomes. Similarly, eighteen studies defining subcompartments within the tumor region were also highlighted to represent the evidence of MR imaging biomarkers. Their reports were critically appraised according to the QUADAS-2 criteria. Results: It has been demonstrated that multi-parametric biomarkers are prepared for surrogating diagnosis, grading, segmentation, overall survival, progression-free survival, recurrence, molecular profiling and response to treatment in gliomas. Quantifications and radiomics features obtained from morphological exams (T1, T2, FLAIR, T1c), PWI (including DSC and DCE), diffusion (DWI, DTI) and chemical shift imaging (CSI) are the preferred MR biomarkers associated to clinical outcomes. Subcompartments relative to the peritumoral region, invasion, infiltration, proliferation, mass effect and pseudo flush, relapse compartments, gross tumor volumes, and high-risk regions have been defined to characterize the heterogeneity. For the majority of pairwise cooccurrences, we found no evidence to assert that observed co-occurrences were significantly different from their expected co-occurrences (Binomial test with False Discovery Rate correction, alpha=0.05). The co-occurrence among terms in the studied papers was found to be driven by their individual prevalence and trends in the literature. Conclusion: Combinations of MR imaging biomarkers from morphological, PWI, DWI and CSI exams have demonstrated their capability to predict clinical outcomes in different management moments of gliomas. Whereas morphologic-derived compartments have been mostly studied during the last ten years, new multi-parametric MRI approaches have also been proposed to discover specific subcompartments of the tumors. MR biomarkers from those subcompartments show the local behavior within the heterogeneous tumor and may quantify the prognosis and response to treatment of gliomas.This work was supported by the Spanish Ministry for Investigation, Development and Innovation project with identification number DPI2016-80054-R.Oltra-Sastre, M.; Fuster García, E.; Juan -Albarracín, J.; Sáez Silvestre, C.; Perez-Girbes, A.; Sanz-Requena, R.; Revert-Ventura, A.... (2019). Multi-parametric MR Imaging Biomarkers Associated to Clinical Outcomes in Gliomas: A Systematic Review. Current Medical Imaging Reviews. 15(10):933-947. https://doi.org/10.2174/1573405615666190109100503S9339471510Louis D.N.; Perry A.; Reifenberger G.; The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016,131(6),803-820Ostrom Q.T.; Gittleman H.; Fulop J.; CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008-2012. Neuro-oncol 2015,17(Suppl. 4),iv1-iv62Yachida S.; Jones S.; Bozic I.; Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010,467(7319),1114-1117Gerlinger M.; Rowan A.J.; Horswell S.; Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012,366(10),883-892Sottoriva A.; Spiteri I.; Piccirillo S.G.M.; Intratumor heterogeneityin human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 2013,110(10),4009-4014Whiting P.F.; Rutjes A.W.; Westwood M.E.; QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011,155(8),529-536Stupp R.; Mason W.P.; van den Bent M.J.; Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005,352(10),987-996Ponte K.F.; Berro D.H.; Collet S.; In vivo relationship between hypoxia and angiogenesis in human glioblastoma: a multimodal imaging study. J Nucl Med 2017,58(10),1574-1579Pope W.B.; Kim H.J.; Huo J.; Recurrent glioblastoma multiforme: ADC histogram analysis predicts response to bevacizumab treatment. Radiology 2009,252(1),182-189Mörén L.; Bergenheim A.T.; Ghasimi S.; Brännström T.; Johansson M.; Antti H.; Metabolomic screening of tumor tissue and serum in glioma patients reveals diagnostic and prognostic information. Metabolites 2015,5(3),502-520Prager A.J.; Martinez N.; Beal K.; Omuro A.; Zhang Z.; Young R.J.; Diffusion and perfusion MRI to differentiate treatment-related changes including pseudoprogression from recurrent tumors in high-grade gliomas with histopathologic evidence. AJNR Am J Neuroradiol 2015,36(5),877-885Kickingereder P.; Burth S.; Wick A.; Radiomic profiling of glioblastoma: identifying an imaging predictor of patient survival with improved performance over established clinical and radiologic risk models. Radiology 2016,280(3),880-889Yoo R-E.; Choi S.H.; Cho H.R.; Tumor blood flow from arterial spin labeling perfusion MRI: a key parameter in distinguishing high-grade gliomas from primary cerebral lymphomas, and in predicting genetic biomarkers in high-grade gliomas. J Magn Reson Imaging 2013,38(4),852-860Liberman G.; Louzoun Y.; Aizenstein O.; Automatic multi-modal MR tissue classification for the assessment of response to bevacizumab in patients with glioblastoma. Eur J Radiol 2013,82(2),e87-e94Ramadan S.; Andronesi O.C.; Stanwell P.; Lin A.P.; Sorensen A.G.; Mountford C.E.; Use of in vivo two-dimensional MR spectroscopy to compare the biochemistry of the human brain to that of glioblastoma. Radiology 2011,259(2),540-549Xintao H.; Wong K.K.; Young G.S.; Guo L.; Wong S.T.; Support vector machine multi-parametric MRI identification of pseudoprogression from tumor recurrence in patients with resected glioblastoma. J Magn Reson Imaging 2011,33(2),296Ingrisch M.; Schneider M.J.; Nörenberg D.; Radiomic Analysis reveals prognostic information in T1-weighted baseline magnetic resonance imaging in patients with glioblastoma. Invest Radiol 2017,52(6),360-366Ulyte A.; Katsaros V.K.; Liouta E.; Prognostic value of preoperative dynamic contrast-enhanced MRI perfusion parameters for high-grade glioma patients. Neuroradiology 2016,58(12),1197-1208O’Neill A.F.; Qin L.; Wen P.Y.; de Groot J.F.; Van den Abbeele A.D.; Yap J.T.; Demonstration of DCE-MRI as an early pharmacodynamic biomarker of response to VEGF Trap in glioblastoma. J Neurooncol 2016,130(3),495-503Kickingereder P.; Bonekamp D.; Nowosielski M.; Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional mr imaging features. Radiology 2016,281(3),907-918Roberto S-R.; Antonio R-V.; Luis M-B.; Angel A-B.; Gracián G-M.; Quantitative mr perfusion parameters related to survival time in high-grade gliomas. European Radiology 2013,23(12),3456-3465Jain R.; Poisson L.; Narang J.; Genomic mapping and survival prediction in glioblastoma: molecular subclassification strengthened by hemodynamic imaging biomarkers. Radiology 2013,267(1),212-220Fathi K.A.; Mohseni M.; Rezaei S.; Bakhshandehpour G.; Saligheh R.H.; Multi-parametric (ADC/PWI/T2-W) image fusion approach for accurate semi-automatic segmentation of tumorous regions in glioblastoma multiforme. MAGMA 2015,28(1),13-22Caulo M.; Panara V.; Tortora D.; Data-driven grading of brain gliomas: a multiparametric MR imaging study. Radiology 2014,272(2),494-503Alexiou G.A.; Zikou A.; Tsiouris S.; Comparison of diffusion tensor, dynamic susceptibility contrast MRI and (99m)Tc-Tetrofosmin brain SPECT for the detection of recurrent high-grade glioma. Magn Reson Imaging 2014,32(7),854-859Van Cauter S.; De Keyzer F.; Sima D.M.; Integrating diffusion kurtosis imaging, dynamic susceptibility-weighted contrast-enhanced MRI, and short echo time chemical shift imaging for grading gliomas. Neuro-oncol 2014,16(7),1010-1021Seeger A.; Braun C.; Skardelly M.; Comparison of three different MR perfusion techniques and MR spectroscopy for multiparametric assessment in distinguishing recurrent high-grade gliomas from stable disease. Acad Radiol 2013,20(12),1557-1565Chawalparit O.; Sangruchi T.; Witthiwej T.; Diagnostic performance of advanced mri in differentiating high-grade from low-grade gliomas in a setting of routine service. J Med Assoc Thai 2013,96(10),1365-1373Li Y.; Lupo J.M.; Parvataneni R.; Survival analysis in patients with newly diagnosed glioblastoma using pre- and postradiotherapy MR spectroscopic imaging. Neuro-oncol 2013,15(5),607-617Shankar J.J.S.; Woulfe J.; Silva V.D.; Nguyen T.B.; Evaluation of perfusion CT in grading and prognostication of high-grade gliomas at diagnosis: a pilot study. AJR Am J Roentgenol 2013,200(5)Zinn P.O.; Mahajan B.; Sathyan P.; Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme. PLoS One 2011,6(10)Matsusue E.; Fink J.R.; Rockhill J.K.; Ogawa T.; Maravilla K.R.; Distinction between glioma progression and post-radiation change by combined physiologic MR imaging. Neuroradiology 2010,52(4),297-306Juan-Albarracín J.; Fuster-Garcia E.; Manjón J.V.; Automated glioblastoma segmentation based on a multiparametric structured unsupervised classification. PLoS One 2015,10(5)Itakura H.; Achrol A.S.; Mitchell L.A.; Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities. Sci Transl Med 2015,7(303)Ion-Margineanu A.; Van Cauter S.; Sima D.M.; Tumour relapse prediction using multiparametric MR data recorded during follow-up of GBM patients. BioMed Res Int 2015,2015Durst C.R.; Raghavan P.; Shaffrey M.E.; Multimodal MR imaging model to predict tumor infiltration in patients with gliomas. Neuroradiology 2014,56(2),107-115Yoon J.H.; Kim J.H.; Kang W.J.; Grading of cerebral glioma with multi-parametric MR Imaging and 18F-FDG-PET: concordance and accuracy. European Radiol 2014,24(2),380-389Demerath T.; Simon-Gabriel C.P.; Kellner E.; Mesoscopic imaging of glioblastomas: are diffusion, perfusion and spectroscopic measures influenced by the radiogenetic phenotype? Neuroradiol J 2017,30(1),36-47Qin L.; Li X.; Stroiney A.; Advanced MRI assessment to predict benefit of anti-programmed cell death 1 protein immunotherapy response in patients with recurrent glioblastoma. Neuroradiology 2017,59(2),135-145Boult J.K.R.; Borri M.; Jury A.; Investigating intracranial tumour growth patterns with multiparametric MRI incorporating Gd-DTPA and USPIO-enhanced imaging. NMR Biomed 2016,29(11),1608-1617Server A.; Kulle B.; Gadmar Ø.B.; Josefsen R.; Kumar T.; Nakstad P.H.; Measurements of diagnostic examination performance using quantitative apparent diffusion coefficient and proton MR spectroscopic imaging in the preoperative evaluation of tumor grade in cerebral gliomas. Eur J Radiol 2011,80(2),462-470Chang P.D.; Chow D.S.; Yang P.H.; Filippi C.G.; Lignelli A.; Predicting glioblastoma recurrence by early changes in the apparent diffusion coefficient value and signal intensity on FLAIR images. AJR Am J Roentgenol 2017,208(1),57-65Yi C.; Shangjie R.; Volume of high-risk intratumoralsubregions at multi-parametric MR imaging predicts overall survival and complements molecular analysis of glioblastoma. Eur Radiol 2017,27,3583-3592Khalifa J.; Tensaouti F.; Chaltiel L.; Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation. Eur Radiol 2016,26(11),4194-4203Prateek P.; Jay P.; Partovi S.; Madabhushi A.; Tiwari P.; Radiomic features from the peritumoral brain parenchyma on treatment-naïve multi-parametric MR imaging predict long versus short-term survival in glioblastomamultiforme: preliminary findings. Eur Radiol 2017,27(10),4188-4197Lemasson B.; Chenevert T.L.; Lawrence T.S.; Impact of perfusion map analysis on early survival prediction accuracy in glioma patients. Transl Oncol 2013,6(6),766-774Inano R.; Oishi N.; Kunieda T.; Visualization of heterogeneity and regional grading of gliomas by multiple features using magnetic resonance-based clustered images. Sci Rep 2016,6,30344Delgado-Goñi T.; Ortega-Martorell S.; Ciezka M.; MRSI-based molecular imaging of therapy response to temozolomide in preclinical glioblastoma using source analysis. NMR Biomed 2016,29(6),732-743Cui Y.; Tha K.K.; Terasaka S.; Prognostic imaging biomarkers in glioblastoma: development and independent validation on the basis of multiregion and quantitative analysis of MR images. Radiology 2016,278(2),546-553Price S.J.; Young A.M.H.; Scotton W.J.; Multimodal MRI can identify perfusion and metabolic changes in the invasive margin of glioblastomas. J Magn Reson Imaging 2016,43(2),487-494Sauwen N.; Acou M.; Van Cauter S.; Comparison of unsupervised classification methods for brain tumor segmentation using multi-parametric MRI. Neuroimage Clin 2016,12,753-764Jena A.; Taneja S.; Gambhir A.; Glioma recurrence versus radiation necrosis: single-session multiparametric approach using simultaneous O-(2-18F-Fluoroethyl)-L-Tyrosine PET/MRI. Clin Nucl Med 2016,41(5),e228-e236Kim H.S.; Goh M.J.; Kim N.; Choi C.G.; Kim S.J.; Kim J.H.; Which combination of MR imaging modalities is best for predicting recurrent glioblastoma? Study of diagnostic accuracy and reproducibility. Radiology 2014,273(3),831-843Christoforidis G.A.; Yang M.; Abduljalil A.; “Tumoral pseudoblush” identified within gliomas at high-spatial-resolution ultrahigh-field-strength gradient-echo MR imaging corresponds to microvascularity at stereotactic biopsy. Radiology 2012,264(1),210-217Wang S.; Kim S.; Chawla S.; Differentiation between glioblastomas, solitary brain metastases, and primary cerebral lymphomas using diffusion tensor and dynamic susceptibility contrast-enhanced MR imaging. AJNR Am J Neuroradiol 2011,32(3),507-514Hanahan D.; Weinberg R.A.; Hallmarks of cancer: the next generation. Cell 2011,144(5),646-674Macdonald D.R.; Cascino T.L.; Schold S.C.; Cairncross J.G.; Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990,8(7),1277-1280Wen P.Y.; Macdonald D.R.; Reardon D.A.; Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 2010,28(11),1963-1972Sorensen A.G.; Batchelor T.T.; Wen P.Y.; Zhang W-T.; Jain R.K.; Response criteria for glioma. Nat Clin Pract Oncol 2008,5(11),634-644Rosenkrantz A.B.; Friedman K.; Chandarana H.; Current status of hybrid PET/MRI in oncologic imaging. AJR Am J Roentgenol 2016,206(1),162-172Castiglioni I.; Gallivanone F.; Canevari C.; Hybrid PET/MRI for In vivo imaging of cancer: current clinical experiences and recent advances. Curr Med Imaging 2016,12,106Mainta I.C.; Perani D.; Delattre B.M.A.; FDG PET/MR imaging in major neurocognitive disorders. Curr Alzheimer Res 2017,14,186-197Marner L.; Henriksen O.M.; Lundemann M.; Larsen V.A.; Law I.; Clinical PET/MRI in neurooncology: opportunities and challenges from a single-institution perspective. Clin Transl Imaging 2017,5(2),135-149R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2015. Available from: https://www.R-project.org

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

Genomic and Functional Approaches to Understanding Cancer Aneuploidy

Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy. Analyzing >10,000 human cancers, Taylor et al. show that aneuploidy is correlated with somatic mutation rate, expression of proliferation genes, and decreased leukocyte infiltration. Loss of chromosome arm 3p is common in squamous cancers, but deletion of chromosome 3p reduces cell proliferation in vitro

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129\u2013283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo. Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes