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

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

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

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Tracing the effects of high-pressure metasomatic fluids and seawater alteration in blueschist-facies overprinted eclogites: Implications for subduction channel processes

Eclogites from the Tian Shan high-pressure/low-temperature (HP/LT) metamorphic belt show evidence for successively increasing metasomatic alteration with increasing retrograde, blueschist-facies overprint. To constrain the source(s) of the metasomatizing fluid and to evaluate elemental and isotopic changes during this overprint, two sequences of eclogite-blueschist transitions were investigated: A layered transition from eclogite to blueschist (FTS 9–1 sequence) and blueschist-facies overprinted pillow metabasalts (FTS 4 samples). Geochemical trends based on the relationships of K, Ba, Rb and Th are consistent with HP metasomatism, but distinct from typical seafloor alteration trends. In contrast, oxygen isotope ratios in garnet (δ18OV-SMOW = 7.3–8.7‰) and omphacite (δ18OV-SMOW = 8.2–9.7‰) are similar to δ18OV-SMOW in bulk low-temperature altered oceanic crust (AOC), suggesting O isotopic preservation of a seafloor alteration signature. Carbonate crystallization related to the metasomatic overprint demonstrate CO2 mobility during subduction and potential C storage in HP metamorphic rocks. Carbon isotope ratios in the two sequences differ markedly: Disseminated calcite in the layered FTS 9–1 sequence has δ13CV-PDB = − 9.14 ± 0.19‰, whereas vein-forming ankerite in the pillow metabasalts has δ13CV-PDB = − 2.08 ± 0.12‰. The ankerite reflects an inorganic marine/hydrothermal signature, as observed in ophiolites, whereas the low δ13CV-PDB values from the calcite point to a contribution of organic carbon. The time when the metasomatic overprint occurred is estimated to be ~ 320 ± 11 Ma based on a Rb-Sr isochron age of six blueschist samples from the pillow metabasalts, which is in agreement with active subduction in this region. Initial (T = 320 Ma) 87Sr/86Sr ratios for all HP/LT rocks range from 0.7059 – 0.7085, and εNd320Ma varies from − 0.4 to + 10.9. Both eclogite-blueschist sequences have initial Sr isotope compositions (87Sr/86Sr ~ 0.707) that are significantly higher than those of typical oceanic mantle-derived basalts. They are thought to derive from a fluid that preserved the Sr isotopic signature of seawater by fluid-rock interaction with seawater-altered oceanic lithosphere in a subduction channel. Mixing models between eclogite and various fluids suggest that the contribution of a sediment-derived fluid was likely less than 20%. A fluid predominantly derived from seawater-altered oceanic lithosphere is also supported by the calculated O isotope composition of the fluids (10.2 – 11.2‰). It is thus evident that subduction channel fluids carry complex, mixed elemental and isotopic signatures, which reflect the composition of their source rocks modified by interaction with various other lithologies. Highlights ► Eclogites from the Tian Shan show blueschist-facies metasomatic overprint ► Fluid-induced metasomatism occurred at 320 ± 11 Ma ► Fluid predominantly derived from seawater-altered oceanic lithosphere ► Carbonates reflect C sequestration of mixture of organic and inorganic component

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies

Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation.

Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation

Molecular characterization and clinical relevance of metabolic expression subtypes in human cancers.

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