Search Results - EGA European Genome-Phenome Archive

Synthetic longitudinal breast cancer whole-genome sequencing dataset

Synthetic longitudinal breast cancer whole-genome sequencing dataset generated at the Barcelona Supercomputing Center (BSC). This study contains fully simulated longitudinal whole-genome sequencing data for one synthetic female breast cancer patient. It includes one matched-normal paired-end sample generated at a nominal depth of 30× and three longitudinal tumour samples generated at a nominal depth of 60×.

Dataset EGAD50000002802

Serafini et al., Nuclear localization of the glutaminyl-tRNA synthetase QARS reveals its role in DNA damage response in ovarian cancer

Uncovering novel mechanisms controlling DNA damage response (DDR) is essential to better understand the molecular features of high-grade serous ovarian cancers (HGSOC), which remain a clinical challenge. Here, we demonstrate that the glutaminyl-tRNA-synthetase QARS is a new key player in DDR. We show that QARS is regulated at translational level by the MAPK pathway in HGSOC and controls homologous recombination (HR) through a translation-independent mechanism. Analyses combining RNA sequencing, immunohistochemistry, proteomic data and functional assays from HGSOC patient cohorts and relevant cellular models reveal that QARS promotes DNA repair via the HR pathway. Interestingly, we uncover that QARS is located in the nucleus and is enriched at chromatin upon DNA damage. Nuclear QARS controls HR by interacting with the nuclear autoantigen SP100, a major component of PML-nuclear bodies (PML-NB), that are regulatory hubs for DNA repair proteins. Our data highlight novel nuclear functions and mechanisms for QARS involving SP100, PML-NB and MRE11 that enhance HR in HGSOC.

Study EGAS50000001968

Genomic platform specific polygenic risk scores impact breast cancer risk stratification

Background: At present, there is no consensus on which genotyping platform should serve as the standard for clinical polygenic risk score (PRS) implementation. Previous studies have compared the overall performance and concordance of different genotyping and sequencing technologies; however, these analyses have generally averaged the results over the whole genome. We evaluated differences in a 313-variant breast cancer PRS (PRS313) across genomic platforms and their impact on risk stratification. Methods: We compare PRS313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes are designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing profiles indels. Concordance of high-risk classification (PRS313scoresum > 0.6) across platforms is assessed using Kappa statistics. Results: In saliva samples, indel concordance with Sanger sequencing varies widely (Kappa: 0.007-1.000). PRS313-ThermoFisher is predictable from other platforms using linear models, despite systematic differences. Greater agreement is observed between arrays with high imputation overlap (e.g., GDA ~ GSA slope=0.986). Agreement in high-risk classification before mean correction is moderate (Fleiss's Kappa=0.552) and improves after mean correction (Kappa=0.650). Arrays with similar designs show higher agreement before mean correction (Kappa=0.745). Mean correction narrows high-risk proportions from 4-45% to 15-21%. Overall, 26 of 92 samples are classified as high risk on at least one platform, but only 7 are high risk across all. When restricting to identical variants across all platforms for PRS313 calculation, the corresponding number of high-risk individuals are 24 and 11. Conclusion: Our findings demonstrate that platform-specific variability can influence PRS313 estimates to potentially reclassify individuals around clinically relevant thresholds.

Study EGAS00001008439

Division of Molecular Oncology, National Cancer Center Research Institute Data Access Committee

Dac EGAC00001001272

RAIDs cervical cancer project

The RAIDS project, launched by the Curie Institute in 2013, aims to molecularly characterize cervical cancer (CC) and improve patient risk stratification. As part of the Bio-RAIDS study (NCT02428842), next-generation sequencing was performed on tumor samples (whole-exome sequencing, shallow whole-genome sequencing and RNA-sequencing) identified frequent alterations, including PIK3CA (30%) and prognostic biomarkers like TERT, linked to poor progression-free survival. Over 50 clinically targetable mutations were found, offering new therapeutic opportunities. Transcriptomic analysis also linked specific genes and pathways to prognosis and tumor necrosis.

Study EGAS50000001012

RAIDs transcriptomic dataset

Here, we describe molecular alterations in 270 cervical cancer patients using 270 tumor frozen samples using RNA-sequencing technology. Tumor samples were obtained from cervical tumor tissue collected at diagnosis. FASTQ files are deposited in the dataset.

Dataset EGAD50000001479

RAIDs Whole Exome Sequencing dataset

Here, we describe molecular alterations in 291 cervical cancer patients using 291 paired tumor and constitutional frozen samples sequenced using Whole Exome Sequencing technology. Tumor samples were obtained from cervical tumor tissue collected at diagnosis. FASTQ files are deposited files are deposited in the dataset

Dataset EGAD50000001480

RAIDs shallow Whole Genome Sequencing dataset

shallow Whole Genome sequencing of 302 patients with cervival cancer. Tissue cervical cancer at diagnosis....

Dataset EGAD50000001481

Colorectal Cancer, NDS Oxford

Data Access Committee governing the terms on which access will be granted to the genotype data generated within the Colorectal Cancer studies research group at the Nuffield Department of Surgical Sciences (NDS), University of Oxford.

Dac EGAC50000001075

Mutational order shapes cell state and chromatin accessibility during early colorectal cancer evolution

Using CRISPR mediated gene editing in patient-derived human colon organoids, we investigate how mutational order shapes cell state and downstream phenotype. We find that loss of FBXW7 on a wild-type background produces minimal phenotypic or transcriptomic change but induces a subtle shift towards a foetal-like, regenerative stem cell identity. Strikingly, the order of mutation acquisition produces markedly different outcomes. 'FA' organoids (i.e. FBXW7 loss preceding APC mutation) retain a near-normal morphology and transcriptional profile. In contrast, 'AF' organoids adopt a proliferative stem cell state and a more transformed phenotype, despite identical final genotype. These differences were associated with distinct chromatin accessibility landscapes, and reflect a cell state-dependent constraint on the transcriptional consequences of subsequent mutations.

Study EGAS50000001945

Canadian prostate cancer samples (CPC-GENE) for PanProstate study

CPC-GENE has sequenced the genomes of 350 intermediate risk prostate cancers to identify genetic signatures that differ in cancers that responded well to treatment compared with those that did not. CPC-GENE also has sequenced multiple regions of prostate cancer from the same gland to determine if and how the genetic make-up of prostate cancer varies within an individual man’s prostate

Study EGAS00001003037

RNA-seq of Breast Cancer Cells in Bone-Mimetic Matrices

Bulk RNA sequencing dataset of four breast cancer cell lines (MDA-MB-231, SCP2, MCF7 and BT-4747) cultured in collagen or in collagen-hydroxyapatite (bone mimetic) matrices to model microenvironment-driven gene expression changes.

Study EGAS50000001966

RNA sequencing of breast cancer cells in collagen and mineralized matrices

The dataset includes 45 FASTQ files generated from RNA sequencing (RNA-seq) of breast cancer cells cultured in monolayer, 3D collagen and 3D mineralized extracellular matrices. RNA-seq libraries were prepared using the Illumina Stranded Total RNA Prep with Ribo-Zero Plus (Illumina). Sequencing was performed on Illumina NextSeq 550 System using NextSeq 500/550 High-Output v2.5 Kit - 150 cycles (Illumina)

Dataset EGAD50000002847

MD Anderson Data Access Committee: Pembrolizumab in Advanced Rare Cancers

Dac EGAC50000000860

Immune-driven response to chemoradiotherapy in POLE-mutated rectal cancer

This study aimed to investigate the chemoradiotherapy response and potential molecular mechanisms underlying chemoradiotherapy response in POLE exonuclease domain mutation-positive rectal cancer.

Study JGAS000919

Research on constructing a genome analysis database for malignant tumors

Germline pathogenic variants (GPVs) in BRCA1/2 are established cancer predisposition factors; however, their biological and clinical significance in gastric cancer (GC) remain unclear. In particular, the directionality and evolutionary timing of locus-specific loss of heterozygosity (LOH) and their relationships with homologous recombination deficiency (HRD) have not been systematically examined in BRCA1/2-associated GC. We conducted integrative genomic analyses of four GCs from BRCA1/2 GPV carriers using tumour-normal tissue paired whole-exome sequencing and allele-specific copy number profiling. LOH directionality was inferred by integrating the variant allele fraction, tumour purity, and locus-specific copy number. The relative timing of LOH events during tumour evolution was estimated, and HRD was evaluated using genome instability scores and mutational signature analyses.

Study JGAS000920

Malignancy of breast cancer cells is increased in a luminal-hybrid state defined by progenitor markers CD146 and keratin 14

We first analyzed a patient-derived xenograft (PDX)-derived breast cancer cell line by dividing cell populations based on CD146-expression by FACS and found that this marker defines a cellular state with increased expression of a selection of luminal hybrid markers, including KRT14. We then knocked out CD146 or KRT14 in another patient-derived xenograft (PDX)-derived breast cancer cell line to investigate further the role of these markers in the hybrid state. For all these populations, we studied their gene expression by bulk RNA sequencing.

Study EGAS50000001972

Transcriptomic characterization of breast cancer cells in a luminal-hybrid state

Background: We have previously identified a subset of early human breast epithelial progenitors that, despite their luminal affiliation, are enriched for basal markers, including CD146 and keratin 14 (K14). This simultaneous presence of both lineages thus defines a luminal-hybrid state. As luminal progenitors are generally proposed as a cell of origin of breast carcinoma, we examined how cells within this luminal hybrid state relate to breast cancer malignancy. Findings: We first analyzed two patient-derived xenograft (PDX)-derived breast cancer cell lines by dividing cell populations based on CD146-expression by FACS and found that this marker defines a cellular state with increased expression of a selection of luminal hybrid markers, including KRT14. When subjecting the sorted cells to in vitro transwell filter analysis, CD146HI/K14HI luminal hybrid state cells were less invasive. Knocking out either CD146- or K14-expression by CRISPR/Cas9 on a CD146/K14-positive background did not affect the in vivo tumorigenic potential, nor the differentiation state. However, when subjecting the respective sorted populations to a soft agar colony formation assay or as in vivo xenografts, CD146HI/K14HI cells exhibited more growth and metastasis, suggesting that the luminal hybrid state contributes to malignant properties. Conclusions: Our findings demonstrate that multiple components of the luminal hybrid state provide distinct properties to tumor malignancy. The fact that breast cancer can reflect a significant part of the original breast gland differentiation hierarchy may add weight to the argument that the search for novel strategies for treating basal-like breast cancer should include manipulation of cellular differentiation states.

Dataset EGAD50000002857

NGS sequencing data of archival FFPE tumor tissue

The aim of the study was to identify mutations in key ovarian cancer genes (BRCA1, BRCA2,TP53, PTEN, ATM, ATR, NF1) in archival fresh-frozen paraffin embedded (FFPE) tumor tissue from platinum-resistant ovarian cancer patients enrolled in the phase I/II GANNET53 clinical trial. From the enrolled 133 patients, archival FFPE tissue was available and DNA was extracted thereof. The DNA samples passing quality control (n=118) were NGS sequenced using the SureSeq™ Ovarian Cancer Panel and the NGS Library Preparation kit (Oxford Gene Technology), which covers all exons of 7 key ovarian cancer genes for single nucleotide variants (SNV) and indels, and the Illumina MiSeq platform. For the paired-end runs, one Read 1 (R1) and one Read 2 (R2) FASTQ file were created for each sample. FASTQ files were compressed and created with the extension .fastq.gz.

Dataset EGAD50000001371

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