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

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

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

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

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies

Terahertz Active Photonic Crystals for Condensed Gas Sensing

The terahertz (THz) spectral region, covering frequencies from 1 to 10 THz, is highly interesting for chemical sensing. The energy of rotational and vibrational transitions of molecules lies within this frequency range. Therefore, chemical fingerprints can be derived, allowing for a simple detection scheme. Here, we present an optical sensor based on active photonic crystals (PhCs), i.e., the pillars are fabricated directly from an active THz quantum-cascade laser medium. The individual pillars are pumped electrically leading to laser emission at cryogenic temperatures. There is no need to couple light into the resonant structure because the PhC itself is used as the light source. An injected gas changes the resonance condition of the PhC and thereby the laser emission frequency. We achieve an experimental frequency shift of 10−3 times the center lasing frequency. The minimum detectable refractive index change is 1.6 × 10−5 RIU

Predictive value of cardiac magnetic resonance right ventricular longitudinal strain in patients with suspected myocarditis

BACKGROUND Recent evidence underlined the importance of right (RV) involvement in suspected myocarditis. We aim to analyze the possible incremental prognostic value from RV global longitudinal strain (GLS) by CMR. METHODS Patients referred for CMR, meeting clinical criteria for suspected myocarditis and no other cardiomyopathy were enrolled in a dual-center register cohort study. Ejection fraction (EF), GLS and tissue characteristics were assessed in both ventricles to assess their association to first major adverse cardiovascular events (MACE) including hospitalization for heart failure (HF), ventricular tachycardia (VT), recurrent myocarditis and death. RESULTS Among 659 patients (62.8% male; 48.1 ± 16.1 years), RV GLS was impaired (> - 15.4%) in 144 (21.9%) individuals, of whom 76 (58%), 108 (77.1%), 27 (18.8%) and 40 (32.8%) had impaired right ventricular ejection fraction (RVEF), impaired left ventricular ejection fraction (LVEF), RV late gadolinium enhancement (LGE) or RV edema, respectively. After a median observation time of 3.7 years, 45 (6.8%) patients were hospitalized for HF, 42 (6.4%) patients died, 33 (5%) developed VT and 16 (2.4%) had recurrent myocarditis. Impaired RV GLS was associated with MACE (HR = 1.07, 95% CI 1.04-1.10; p < 0.001), HF hospitalization (HR = 1.17, 95% CI 1.12-1.23; p < 0.001), and death (HR = 1.07, 95% CI 1.02-1.12; p = 0.004), but not with VT and recurrent myocarditis in univariate analysis. RV GLS lost its association with outcomes, when adjusted for RVEF, LVEF, LV GLS and LV LGE extent. CONCLUSION RV strain is associated with MACE, HF hospitalization and death but has neither independent nor incremental prognostic value after adjustment for RV and LV function and tissue characteristics. Therefore, assessing RV GLS in the setting of myocarditis has only limited value

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