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• Genetic and epigenetic characterization of adenoid cystic carcinoma

  Whole genome sequences of ACC primagrafts, Histone modification maps and transcription factor binding maps for ACC primagrafts and primary tumors. Processed ChIP-seq data is available on GEO under accession number GSE76465.

  Dataset EGAD00001001662

• BRIDGE SPEED April 2016

  Whole genome sequencing CRAM files for four samples from the BRIDGE Consortium (SPEED project) with pathogenic variants in a gene associated with a movement disorder.

  Dataset EGAD00001002070

• Transcriptome profiling for Korean Early Onset Gastric Cancer

  To identify transcriptome profile in this unique subset of gastric cancers, RNA-seq analyses were performed using frozen cancer tissue. Adjacent normal tissue of the same patients were used in differently expressed gene selection and fusion gene prediction.

  Dataset EGAD00001002187

• Single-cell Transcriptome for glioblastoma intra-tumoral heterogeneity

  Single-Cell RNA Sequencing of 355 cells isolated from 7 tissue fragments of 3 patients corresponding to locally adjacent tumor, multifocal with recurrence and sections segregated by a marker of tumor cellularity (5-ALA).

  Dataset EGAD00001002249

• Rapid Early Action for Coronary Treatment (REACT-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: This multicenter controlled community study developed and evaluated the impact of a community educational intervention program on participant delay time from onset of symptoms of an acute myocardial infarction (AMI) to arrival at a hospital emergency department.Background: Although early reperfusion or thrombolytic therapy can reduce morbidity and mortality following an AMI, delayed access to medical care in participants is relatively common. Mean delay times from symptom onset to hospital arrival range from more than 4 hours to 24 hours, and the largest component of prolonged delay is participant recognition and action.Participants: A total of 20 communities from 5 field centers in the U.S. were pair-matched (10 pairs) according to geographic proximity and demographic characteristics. After initiation of a 4 month baseline surveillance period, one community in each pair was randomly selected to receive the intervention. The baseline surveillance period was followed by an 18 month community intervention and surveillance period. The community surveillance captured a total of 59,944 adults aged 30 years or older presenting to hospital emergency departments with chest pain, of whom 20,364 met study criteria for suspected acute coronary heart disease (CHD) at admission and discharged with a CHD diagnosis.Conclusions: Delay times were decreased in the intervention and reference communities. The results showed that the multicomponent community intervention program did not differentially reduce delay time from onset of AMI symptoms to arrival at a hospital, but did significantly increase the use of Emergency Medical Services by these participants in the intervention communities. (PMID:10872014).

  Study phs003885

• How upcycled prostate cancer sequences enabled key findings on telomeres length

  The length of telomeres, the chromosomes’ end tails, as depicted in the figure below, physiologically shorten with aging. This means that younger cells have longer telomeres compared to their aged counterparts; one could say that the length of cells’ telomeres is a measure of their replicative power. Cancer cells are known to be able to turn this into their favour, and expand their replicative immortality through telomere lengthening and maintenance. Despite being a well-studied pan-cancer hallmark, the relation of the telomeres length to specific cancer genomic features is poorly understood. Julia Livingstone and her colleagues from P.C. Boutros' team in Los Angeles focused their work on prostate cancer. To investigate the relations between telomere length and the clinico-genomics of prostate tumours, they used whole genome sequencing (WGS) of 392 published tumour–reference pairs previously deposited at the EGA under accession numbers EGAS00001000400 and EGAS00001000900. Their work was published on Nature Communications in November 2021. They determined the telomere length of the sequencing sample, from both tumour and non-tumour adjacent tissues, and subsequently ran statistical analysis to investigate possible correlation between the telomeres length with several cancer features. The team discovered that telomeres length does not correlate with any specific driver gene mutation, but it does with the overall frequency of single nucleotides variants in a sample. This finding suggests that tumours with shorter telomeres accumulate more mutations without strong selective pressures for specific ones. While proliferation rate did not correlate directly with telomere length, methylation of almost half of all genes strongly did. The team’s results are massive and reveal a complicated and fascinating relation of different clinical and genomic features of prostate cancer with telomere length. In the paper discussion, they smartly consider different possibilities. As noted above, all these amazing results have been obtained analysing previously sequenced samples. Remarkably, the researchers who generated the samples did not focus at all on telomeres length. They indeed studied specific genes mutations and the features of early and late-onset prostate cancer. This proves, once again, the power of sequencing data re-use. This data is tremendously rich in information, and can hardly be exhausted with any number of analyses. Generating sequencing data, especially Whole Genome Sequencing, even better if tumor-reference paired, is like shopping every last article at the grocery store. You can then cook several recipes, or prepare a seven-course dinner, and still have ingredients left for someone else to borrow and cook something you have not thought about, a recipe that is just not in your cookbook. Noteworthy, the data retrieved from the EGA for this paper is associated with rich and complete metadata, meaning pheno-clinical information regarding the sample donors. As Julia Livingstone and her team wrote, using rich clinical annotations enabled them to assess the relationship between telomere length and patients outcome. This highlights once again the importance of reporting and annotating metadata correctly; It might feel like extra work for the researchers depositing their data, but it really has a huge value. Our team at the EGA is currently working to improve the metadata annotation process, with the aim to maximize the benefits for the scientific community.

  Blog prostate-cancer-sequences-enabled-key-findings-on-telomeres-length

• Bone marrow breakout lesions act as key sites for tumor-immune cell diversification and exhaustion in multiple myeloma

  Multiple myeloma is a disease characterized by the expansion of cancerous plasma cells in the bone marrow. The bone marrow microenvironment plays a pivotal role in supporting myeloma growth and modulating tumor immunity. As the disease progresses, myeloma cells may become independent of the bone marrow environment, leading to extramedullary disease associated with poor prognosis. However, the early processes associated with bone marrow independence and its implications for disease and immune control remain poorly understood. Here, we employed comprehensive single-cell and spatial mapping to identify the disruption of the cortical bone and subsequent expansion of myeloma cells in breakout lesions as a key event in multiple myeloma pathogenesis and tumor immunity. Breakout lesions harbor an adapted niche and a unique immune microenvironment conferred by sustained immune-tumor interactions. In particular, tumor-reactive T cells with a highly exhausted phenotype, alongside unique NK cell and macrophage subtypes, specifically expanded in breakout lesions. Spatially-resolved genomic, transcriptomic and cellular analyses uncovered extensive intra-lesion heterogeneity, suggesting a divergent co-evolution of genomic variation and locally confined T cell responses in distinct subregions. Ultra-high plex imaging revealed that tumor-reactive T cells, together with other immune-regulatory cells and dendritic cells, co-expand and exhaust upon sustained tumor interactions in locally confined immune islands. In contrast, immune-regulatory macrophage and NK cell subsets operate spatially separated within myeloma cell deserts. Jointly, our analyses uncover bone marrow breakout lesions as a hotspot for tumor-immune cell interactions, diversification and exhaustion, representing a key event in myeloma pathogenesis with significant therapeutic implications.

  Study EGAS50000000304

• Genetic Risk for Subsequent Neoplasms among Long-term Survivors of Childhood Cancer in the St. Jude Lifetime Cohort

  While childhood cancer survivors are known to be at increased risk of subsequent neoplasms (SNs), the contribution of germline mutations in cancer predisposition genes to the risk of SN is largely unknown. Whole-genome sequencing (30X) was performed on 3,006 5+ year survivors of childhood cancer (median age, 35.8 [range: 7.1-69.8] years) from the St. Jude Lifetime Cohort. Survivors underwent a comprehensive clinical assessment. Germline mutations in 156 cancer predisposition genes (SJCPG156), including a subset of 60 (SJCPG60) autosomal dominant genes with moderate to high penetrance, were classified for their pathogenicity. Piecewise exponential regression, stratified by radiation exposure, was used to evaluate the relative rate (RR) and 95% confidence interval (95% CI) of SN occurrence by mutation status. Pathogenic or likely pathogenic mutations in SJCPG156 and SJCPG60 were identified in 11.7% and 5.8% of survivors, respectively. The most frequently mutated SJCPG60 genes included RB1 (n=43), NF1 (n=22), BRCA2 (n=14), BRCA1 (n=12) and TP53 (n=10). Mutations in SJCPG60 were associated with the rate of subsequent sarcoma (RR, 10.3; 95% CI, 4.2 to 25.6) and breast cancer (RR, 13.3; 95% CI, 5.8 to 30.5) among irradiated survivors, and the rate of developing any SN (RR, 4.8; 95% CI, 2.4 to 9.4) and breast cancer (RR, 7.8; 95% CI, 2.5 to 24.0) among non-irradiated survivors. The rate of developing ≥2 histologically distinct SNs was increased 17.8-fold (95% CI, 3.5 to 89.8) among SJCPG60 mutation carriers treated without radiotherapy. Similar but attenuated associations were observed for mutations in SJCPG156. Survivors who develop a SN without prior radiotherapy or who are diagnosed with a subsequent sarcoma or breast cancer within a site of prior radiotherapy should be referred to genetic counseling.

  Study EGAS00001002499

• European BestAgeing Study on microRNA candidates for cardiovascular disease

  Background: Circulating miRNAs have emerged as promising biomarker candidates due to their stability and their role in regulating key pathological pathways in cardiovascular disease (CVD). Yet, large-scale, multicenter studies examining their diagnostic and prognostic potential are scarce. This study evaluates the potential of miRNA expression profiles to inform disease classification and risk stratification across major CVD phenotypes, including acute coronary syndrome (ACS), chronic coronary artery disease (CAD), dilated cardiomyopathy (DCM), and ischemic cardiomyopathy (ICM), in a large, multicenter European cohort. Methods: We assessed genome-wide miRNA expression profiles in a total of 1,209 cardiovascular patients and 848 controls in a uniform, standardized fashion, which renders this study one of the largest prospective miRNA studies. To focus on only the most biologically plausible miRNAs for clinical translation, we mined all original studies of miRNA candidates in CVD and performed differential miRNA expression and enrichment analysis. We then trained disease-specific binary classification models to evaluate the diagnostic potential of miRNA signatures. Finally, we evaluated prognosis and disease severity based on distinct miRNA levels. Results: 634 original abstracts were identified, detailing 166 ACS, 181 CAD, 56 DCM, and 182 ICM miRNAs. Without further optimization, the signatures of a priori miRNAs already yielded very good diagnostic performance with ROC AUC of 0.83 – 0.95. There was an improvement when considering additional miRNAs in a discovery setting. Interestingly, in ACS, CAD and DCM we observed a significantly worse prognosis in probands with higher scores in the miRNA signatures, indicating additional prognostic information. Conclusions: The European BestAgeing miRNA study reveals emerging associations of several miRNA signatures with cardiovascular disease discrimination and prognostication, providing a foundation for future external validation and potential clinical translation of this class of markers.

  Study EGAS00001008346

• Comparison of capture-based method for transcriptome profiling of formalin-fixed paraffin embedded tumor samples

  Background: The need for fresh frozen (FF) tissue limits implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. Methods: Transcriptomic analysis of 32 FFPE tumor samples from 11 patients was performed using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. Results: The Spearman's correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72-0.9, p < 0.05). A significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05) was observed. All exome capture-based methods reliably detected outlier expression of actionable genes, including ERBB2, MET, NTRK1, and PPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen's k = 0.7, p < 0.01). Both Agilent and IDT detected all the clinically relevant fusions that were initially identified in FF-TruSeq. Conclusion: All exome capture-based methods had comparable performance and concordance with FF-TruSeq. By enabling the interrogation of FFPE tumor samples, our findings will enable the implementation of RNA-seq in the clinic to guide precision oncology approaches.

  Study EGAS00001005255