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

Genome-wide meta-analysis of myopia and hyperopia provides evidence for replication of 11 loci

Refractive error (RE) is a complex, multifactorial disorder characterized by a mismatch between the optical power of the eye and its axial length that causes object images to be focused off the retina. The two major subtypes of RE are myopia (nearsightedness) and hyperopia (farsightedness), which represent opposite ends of the distribution of the quantitative measure of spherical refraction. We performed a fixed effects meta-analysis of genome-wide association results of myopia and hyperopia from 9 studies of European-derived populations: AREDS, KORA, FES, OGP-Talana, MESA, RSI, RSII, RSIII and ERF. One genome-wide significant region was observed for myopia, corresponding to a previously identified myopia locus on 8q12 (p = 1.25610-8), which has been reported by Kiefer et al. as significantly associated with myopia age at onset and Verhoeven et al. as significantly associated to mean spherical-equivalent (MSE) refractive error. We observed two genomewide significant association

The Occurrence of Rocky Habitable-zone Planets around Solar-like Stars from Kepler Data

We present the occurrence rates for rocky planets in the habitable zones (HZs) of main-sequence dwarf stars based on the Kepler DR25 planet candidate catalog and Gaia-based stellar properties. We provide the first analysis in terms of star-dependent instellation flux, which allows us to track HZ planets. We define η⊕ as the HZ occurrence of planets with radii between 0.5 and 1.5 R⊕ orbiting stars with effective temperatures between 4800 and 6300 K. We find that η⊕ for the conservative HZ is between 0.37^(+0.48)_(−0.21) (errors reflect 68% credible intervals) and 0.60^(+0.90)_(−0.36) planets per star, while the optimistic HZ occurrence is between 0.58^(+0.73)_(−0.33) and 0.88^(+1.28)_(−0.51) planets per star. These bounds reflect two extreme assumptions about the extrapolation of completeness beyond orbital periods where DR25 completeness data are available. The large uncertainties are due to the small number of detected small HZ planets. We find similar occurrence rates between using Poisson likelihood Bayesian analysis and using Approximate Bayesian Computation. Our results are corrected for catalog completeness and reliability. Both completeness and the planet occurrence rate are dependent on stellar effective temperature. We also present occurrence rates for various stellar populations and planet size ranges. We estimate with 95% confidence that, on average, the nearest HZ planet around G and K dwarfs is ~6 pc away and there are ~4 HZ rocky planets around G and K dwarfs within 10 pc of the Sun

The Occurrence of Rocky Habitable Zone Planets Around Solar-Like Stars from Kepler Data

We present occurrence rates for rocky planets in the habitable zones (HZ) of main-sequence dwarf stars based on the Kepler DR25 planet candidate catalog and Gaia-based stellar properties. We provide the first analysis in terms of star-dependent instellation flux, which allows us to track HZ planets. We define $\eta_\oplus$ as the HZ occurrence of planets with radius between 0.5 and 1.5 $R_\oplus$ orbiting stars with effective temperatures between 4800 K and 6300 K. We find that $\eta_\oplus$ for the conservative HZ is between $0.37^{+0.48}_{-0.21}$ (errors reflect 68\% credible intervals) and $0.60^{+0.90}_{-0.36}$ planets per star, while the optimistic HZ occurrence is between $0.58^{+0.73}_{-0.33}$ and $0.88^{+1.28}_{-0.51}$ planets per star. These bounds reflect two extreme assumptions about the extrapolation of completeness beyond orbital periods where DR25 completeness data are available. The large uncertainties are due to the small number of detected small HZ planets. We find similar occurrence rates using both a Poisson likelihood Bayesian analysis and Approximate Bayesian Computation. Our results are corrected for catalog completeness and reliability. Both completeness and the planet occurrence rate are dependent on stellar effective temperature. We also present occurrence rates for various stellar populations and planet size ranges. We estimate with $95\%$ confidence that, on average, the nearest HZ planet around G and K dwarfs is about 6 pc away, and there are about 4 HZ rocky planets around G and K dwarfs within 10 pc of the Sun.Comment: To appear in The Astronomical Journa

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

SummaryWe report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development