The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large ...number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.
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•Systematic analysis of enhancer expression across ∼9,000 samples of 33 cancer types•Global enhancer activation positively correlates with aneuploidy but not mutations•A computational method that infers causal enhancer-target-gene relationships•Enhancers as key regulators of therapeutic targets, including PD-L1
Causal enhancer-target-gene relationships are inferred from a systematic analysis of 33 cancer types.
Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including ...the most detailed analysis of
alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with
and
mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene
in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with
and
mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene
in epithelioid MPM.
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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.
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•119 splicing factor genes carry putative driver mutations in one or more cancer types•BLCA and UVM carry more driver splicing factor mutations than expected by chance•Common splicing factor mutations associated with lineage-independent altered splicing•Mutations are associated with deregulation of cell-autonomous pathways and immune infiltration
Seiler et al. report that 119 splicing factor genes carry putative driver mutations over 33 tumor types in TCGA. The most common mutations appear to be mutually exclusive and are associated with lineage-independent altered splicing. Samples with these mutations show deregulation of cell-autonomous pathways and immune infiltration.
We performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic ...mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified.
•Uterine carcinosarcomas (UCSs) have frequent TP53 mutations•UCSs demonstrate a strong and varied degree of epithelial-mesenchymal transition•MicroRNA expression in UCSs is under epigenetic control•Multiple alterations are present in UCSs in genes that are therapeutic targets
Cherniack et al. perform integrated molecular analyses of uterine carcinosarcomas and identify alterations in canonical pathways containing therapeutic targets currently in clinical trials. They also dissect the interaction between genomic and epigenomic regulations of epithelial-to-mesenchymal transition.
This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human ...papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.
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•SCCs show chromosome or methylation alterations affecting multiple related genes•These regulate squamous stemness, differentiation, growth, survival, and inflammation•Copy-quiet SCCs have hypermethylated (FANCF, TET1) or mutated (CASP8, MAPK-RAS) genes•Potential targets include ΔNp63, WEE1, IAPs, PI3K-mTOR/MAPK, and immune responses
Campbell et al. reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations. These affect squamous cell pathways and programs that provide candidates for therapy.
We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a ...paucity of somatic mutations. Somatic mutation of only three genes achieved significance—KIT, KRAS, and NRAS—exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas.
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•KIT-mutated seminoma has distinct DNA methylation and immune infiltration profiles•DNA methylation and miRNA expression differ greatly between histology types•Significant somatic mutations are present only in TGCTs with seminoma components•All histology types exhibit extensive aneuploidy and low mutation frequency
Shen et al. identify molecular characteristics that classify testicular germ cell tumor types, including a separate subset of seminomas defined by KIT mutations. This provides a set of candidate biomarkers for risk stratification and potential therapeutic targeting.
Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA ...expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
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•IDH mutant CCAs have distinct mRNA, copy number, and DNA methylation features•IDH mutant CCAs display high mitochondrial and low chromatin modifier gene expression•IDH mutant CCAs methylate the ARID1A promoter and show low ARID1A expression•Other IDH mutant liver cancers show multiplatform similarities to CCA
Farshidfar et al. present The Cancer Genome Atlas (TCGA) marker analysis of cholangiocarcinoma. Through multi-platform analyses, they identify a distinct subtype enriched for IDH mutants. This subtype shows increased mitochondrial and decreased chromatin modifier gene expression, including potential epigenetic silencing of ARID1A. Other IDH-mutant liver cancers molecularly resemble cholangiocarcinoma.
The Cancer Genome Atlas (TCGA) cancer genomics dataset includes over 10,000 tumor-normal exome pairs across 33 different cancer types, in total >400 TB of raw data files requiring analysis. Here we ...describe the Multi-Center Mutation Calling in Multiple Cancers project, our effort to generate a comprehensive encyclopedia of somatic mutation calls for the TCGA data to enable robust cross-tumor-type analyses. Our approach accounts for variance and batch effects introduced by the rapid advancement of DNA extraction, hybridization-capture, sequencing, and analysis methods over time. We present best practices for applying an ensemble of seven mutation-calling algorithms with scoring and artifact filtering. The dataset created by this analysis includes 3.5 million somatic variants and forms the basis for PanCan Atlas papers. The results have been made available to the research community along with the methods used to generate them. This project is the result of collaboration from a number of institutes and demonstrates how team science drives extremely large genomics projects.
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•Exome sequencing-based variant calls from 10,000 individuals•Samples from 33 cancer types•Variants from: MuTect, MuSE, VarScan2, Radia, Pindel, Somatic Sniper, Indelocator
The MC3 is a variant calling project of over 10,000 cancer exome samples from 33 cancer types. Over three million somatic variants were detected using seven different methods developed from institutions across the United States. These variants formed the basis for the PanCan Atlas papers.
Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer ...types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.
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•Classification of metabolic expression subtypes in 33 TCGA cancer types•Metabolic expression subtypes show consistent prognostic patterns across cancer types•Analysis of master regulators of metabolic subtypes suggesting therapeutic targets•Metabolic expression subtypes associated with sensitivity to drugs in clinical use
Peng et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to characterize tumor subtypes based on the expression of seven metabolic pathways. They find metabolic expression subtypes are associated with patient survivals and suggest the therapeutic and predictive relevance of subtype-related master regulators.
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.
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•Hundreds of lncRNAs target cancer genes and pathways in each tumor context•lncRNA copy numbers are predictive of target cancer gene dysregulation•Most lncRNAs are predicted to be transcriptional or post-transcriptional specialists•lncRNAs are predicted to synergistically regulate proliferation pathways in cancer
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.
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