An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Paradoxical family practices: LGBTQ+ young people, mental health and wellbeing

This article will explore how LGBTQ+ young people sustain, and in some cases survive, family relationships. We develop the concept of ‘paradoxical family practices’ and use this to demonstrate the ways in which LGBTQ+ young people manage family life through everyday emotion work. This highlights: (1) how families ordinarily navigate heteronormativity and ‘issues’ of gender/sexuality; (2) the efficacy of ‘paradoxical family practices’ as a conceptual tool; (3) the value of emotion-centred multiple qualitative methods to explore the lives of LGBTQ+ young people and mental health. Findings derive from a small-scale UK study funded by the Wellcome Trust (UNS39780) and were generated through a two-stage methodology comprising digital/paper emotion maps and qualitative interviews with LGBTQ+ young people aged 16–25 (n = 12) followed by diary methods and follow-up interviews (n = 9). Interviews were also completed with ‘family members’ (n = 7)

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Euclid preparation: XVIII. The NISP photometric system

Galaxie

Euclid preparation: XXX. Performance assessment of the NISP red grism through spectroscopic simulations for the wide and deep surveys

This work focusses on the pilot run of a simulation campaign aimed at investigating the spectroscopic capabilities of the Euclid Near-Infrared Spectrometer and Photometer (NISP), in terms of continuum and emission line detection in the context of galaxy evolutionary studies. To this purpose, we constructed, emulated, and analysed the spectra of 4992 star-forming galaxies at 0.3 ≤ z ≤ 2.5 using the NISP pixel-level simulator. We built the spectral library starting from public multi-wavelength galaxy catalogues, with value-added information on spectral energy distribution (SED) fitting results, and stellar population templates from Bruzual & Charlot (2003, MNRAS, 344, 1000). Rest-frame optical and near-IR nebular emission lines were included using empirical and theoretical relations. Dust attenuation was treated using the Calzetti extinction law accounting for the differential attenuation in line-emitting regions with respect to the stellar continuum. The NISP simulator was configured including instrumental and astrophysical sources of noise such as the dark current, read-out noise, zodiacal background, and out-of-field stray light. In this preliminary study, we avoided contamination due to the overlap of the slitless spectra. For this purpose, we located the galaxies on a grid and simulated only the first order spectra. We inferred the 3.5σ NISP red grism spectroscopic detection limit of the continuum measured in the H band for star-forming galaxies with a median disk half-light radius of 0.″4 at magnitude H = 19.5 ± 0.2 AB mag for the Euclid Wide Survey and at H = 20.8 ± 0.6 AB mag for the Euclid Deep Survey. We found a very good agreement with the red grism emission line detection limit requirement for the Wide and Deep surveys. We characterised the effect of the galaxy shape on the detection capability of the red grism and highlighted the degradation of the quality of the extracted spectra as the disk size increased. In particular, we found that the extracted emission line signal-to-noise ratio (S/N) drops by ~45% when the disk size ranges from 0.″25 to 1″. These trends lead to a correlation between the emission line S/N and the stellar mass of the galaxy and we demonstrate the effect in a stacking analysis unveiling emission lines otherwise too faint to detect.Key words: surveys / Galaxy: evolution / galaxies: formation / galaxies: star formation / techniques: spectroscopic / instrumentation: detectors</p

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

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

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

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

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. 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