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

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

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

Group-based parent training programmes for improving emotional and behavioural adjustment in young children

BackgroundEmotional and behavioural problems in children are common. Research suggests that parenting has an important role to play in helping children to become well-adjusted, and that the first few months and years are especially important. Parenting programmes may have a role to play in improving the emotional and behavioural adjustment of infants and toddlers, and this review examined their effectiveness with parents and carers of young children.Objectives1. To establish whether group-based parenting programmes are effective in improving the emotional and behavioural adjustment of young children (maximum mean age of three years and 11 months); and2. To assess whether parenting programmes are effective in the primary prevention of emotional and behavioural problems.Search methodsIn July 2015 we searched CENTRAL (the Cochrane Library), Ovid MEDLINE, Embase (Ovid), and 10 other databases. We also searched two trial registers and handsearched reference lists of included studies and relevant systematic reviews.Selection criteriaTwo reviewers independently assessed the records retrieved by the search. We included randomised controlled trials (RCTs) and quasi-RCTs of group-based parenting programmes that had used at least one standardised instrument to measure emotional and behavioural adjustment in children.Data collection and analysisOne reviewer extracted data and a second reviewer checked the extracted data. We presented the results for each outcome in each study as standardised mean differences (SMDs) with 95% confidence intervals (CIs). Where appropriate, we combined the results in a meta-analysis using a random-effects model. We used the GRADE (Grades of Recommendations, Assessment, Development, and Evaluation) approach to assess the overall quality of the body of evidence for each outcome.Main resultsWe identified 22 RCTs and two quasi-RCTs evaluating the effectiveness of group-based parenting programmes in improving the emotional and behavioural adjustment of children aged up to three years and 11 months (maximum mean age three years 11 months).The total number of participants in the studies were 3161 parents and their young children. Eight studies were conducted in the USA, five in the UK, four in Canada, five in Australia, one in Mexico, and one in Peru. All of the included studies were of behavioural, cognitive-behavioural or videotape modelling parenting programmes.We judged 50% (or more) of the included studies to be at low risk for selection bias, detection bias (observer-reported outcomes), attrition bias, selective reporting bias, and other bias. As it is not possible to blind participants and personnel to the type of intervention in these trials, we judged all studies to have high risk of performance bias. Also, there was a high risk of detection bias in the 20 studies that included parent-reported outcomes.The results provide evidence that group-based parenting programmes reduce overall emotional and behavioural problems (SMD -0.81, 95% CI -1.37 to -0.25; 5 studies, 280 participants, low quality evidence) based on total parent-reported data assessed at postintervention. This result was not, however, maintained when two quasi-RCTs were removed as part of a sensitivity analysis (SMD -0.67, 95% CI -1.43 to 0.09; 3 studies, 221 participants). The results of data from subscales show evidence of reduced total externalising problems (SMD -0.23, 95% CI -0.46 to -0.01; 8 studies, 989 participants, moderate quality evidence). Single study results show very low quality evidence of reductions in externalising problems hyperactivity-inattention subscale (SMD -1.34; 95% CI -2.37 to -0.31; 19 participants), low quality evidence of no effect on total internalising problems (SMD 0.34; 95% CI -0.12 to 0.81; 73 participants), and very low quality evidence of an increase in social skills (SMD 3.59; 95% CI 2.42 to 4.76; 32 participants), based on parent-reported data assessed at postintervention. Results for secondary outcomes, which were also measured using subscales, show an impact on parent-child interaction in terms of reduced negative behaviour (SMD -0.22, 95% CI -0.39 to -0.06; 7 studies, 941 participants, moderate quality evidence), and improved positive behaviour (SMD 0.48, 95% CI 0.17 to 0.79; 4 studies, 173 participants, moderate quality evidence) as rated by independent observers postintervention. No further meta-analyses were possible. Results of subgroup analyses show no evidence for treatment duration (seven weeks or less versus more than eight weeks) and inconclusive evidence for prevention versus treatment interventions.Authors' conclusionsThe findings of this review, which relate to the broad group of universal and at-risk (targeted) children and parents, provide tentative support for the use of group-based parenting programmes to improve the overall emotional and behavioural adjustment of children with a maximum mean age of three years and 11 months, in the short-term. There is, however, a need for more research regarding the role that these programmes might play in the primary prevention of both emotional and behavioural problems, and their long-term effectiveness

Depressive and anxiety disorders and antidepressant prescriptions among insured children and young adults with congenital adrenal hyperplasia in the United States

BackgroundDysfunction in the hypothalamic-pituitary-adrenal axis has been associated with depressive and anxiety disorders. Little is known about the risk for these disorders among individuals with congenital adrenal hyperplasia (CAH), a form of primary adrenal insufficiency.ObjectiveWe investigated the prevalence of depressive and anxiety disorders and antidepressant prescriptions in two large healthcare databases of insured children, adolescents, and young adults with CAH in the United States.MethodsWe conducted a retrospective cohort study using administrative data from October 2015 through December 2019 for individuals aged 4–25 years enrolled in employer-sponsored or Medicaid health plans.ResultsAdjusting for age, the prevalence of depressive disorders [adjusted prevalence ratio (aPR) = 1.7, 95% confidence interval (CI): 1.4-2.0, p<0.001], anxiety disorders [aPR = 1.7, 95% CI: 1.4-1.9, p<0.001], and filled antidepressant prescriptions [aPR = 1.7, 95% CI: 1.4-2.0, p<0.001] was higher among privately insured youth with CAH as compared to their non-CAH peers. Prevalence estimates were also higher among publicly insured youth with CAH for depressive disorders [aPR = 2.3, 95% CI: 1.9-2.9, p<0.001], anxiety disorders [aPR = 2.0, 95% CI: 1.6-2.5, p<0.001], and filled antidepressant prescriptions [aPR = 2.5, 95% CI: 1.9-3.1, p<0.001] as compared to their non-CAH peers.ConclusionsThe elevated prevalence of depressive and anxiety disorders and antidepressant prescriptions among youth with CAH suggests that screening for symptoms of depression and anxiety among this population might be warranted

Studying the Functional Genomics of Stress Responses in Loblolly Pine With the Expresso Microarray Experiment Management System

Conception, design, and implementation of cDNA microarray experiments present a variety of bioinformatics challenges for biologists and computational scientists. The multiple stages of data acquisition and analysis have motivated the design of Expresso, a system for microarray experiment management. Salient aspects of Expresso include support for clone replication and randomized placement; automatic gridding, extraction of expression data from each spot, and quality monitoring; flexible methods of combining data from individual spots into information about clones and functional categories; and the use of inductive logic programming for higher-level data analysis and mining. The development of Expresso is occurring in parallel with several generations of microarray experiments aimed at elucidating genomic responses to drought stress in loblolly pine seedlings. The current experimental design incorporates 384 pine cDNAs replicated and randomly placed in two specific microarray layouts. We describe the design of Expresso as well as results of analysis with Expresso that suggest the importance of molecular chaperones and membrane transport proteins in mechanisms conferring successful adaptation to long-term drought stress

Deregulation of MYCN, LIN28B and LET7 in a Molecular Subtype of Aggressive High-Grade Serous Ovarian Cancers

Molecular subtypes of serous ovarian cancer have been recently described. Using data from independent datasets including over 900 primary tumour samples, we show that deregulation of the Let-7 pathway is specifically associated with the C5 molecular subtype of serous ovarian cancer. DNA copy number and gene expression of HMGA2, alleles of Let-7, LIN28, LIN28B, MYC, MYCN, DICER1, and RNASEN were measured using microarray and quantitative reverse transcriptase PCR. Immunohistochemistry was performed on 127 samples using tissue microarrays and anti-HMGA2 antibodies. Fluorescence in situ hybridisation of bacterial artificial chromosomes hybridized to 239 ovarian tumours was used to measure translocation at the LIN28B locus. Short interfering RNA knockdown in ovarian cell lines was used to test the functionality of associations observed. Four molecular subtypes (C1, C2, C4, C5) of high-grade serous ovarian cancers were robustly represented in each dataset and showed similar pattern of patient survival. We found highly specific activation of a pathway involving MYCN, LIN28B, Let-7 and HMGA2 in the C5 molecular subtype defined by MYCN amplification and over-expression, over-expression of MYCN targets including the Let-7 repressor LIN28B, loss of Let-7 expression and HMGA2 amplification and over-expression. DICER1, a known Let-7 target, and RNASEN were over-expressed in C5 tumours. We saw no evidence of translocation at the LIN28B locus in C5 tumours. The reported interaction between LIN28B and Let-7 was recapitulated by siRNA knockdown in ovarian cancer cell lines. Our results associate deregulation of MYCN and downstream targets, including Let-7 and oncofetal genes, with serous ovarian cancer. We define for the first time how elements of an oncogenic pathway, involving multiple genes that contribute to stem cell renewal, is specifically altered in a molecular subtype of serous ovarian cancer. By defining the drivers of a molecular subtype of serous ovarian cancers we provide a novel strategy for targeted therapeutic intervention

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