11988 results for "cancer rna-seq"

in 27.66 milliseconds.

• A Therapeutic Vaccine for Fibrolamellar Hepatocellular Carcinoma

  Fibrolamellar hepatocellular carcinoma (FLC) is a rare form of liver cancer affecting 33 children and young adults that is driven by a chimeric protein, DNAJ-PKAc. We conducted a phase 1 clinical trial of a therapeutic vaccine targeting DNAJ-PKAc 38 (FLC-Vac), in combination with nivolumab and ipilimumab, in children and adults with advanced FLC. Among 16 patients enrolled, 12 completed the vaccine priming phase and were evaluable for both immunological and clinical endpoints. Grade 3 treatment-related adverse events were reported by six patients (37.5%). DNAJ43 PKAc-specific T cell responses were detected in 9/12 patients after treatment. In the subset of patients who completed the initial priming phase the disease control rate (DCR) was 75% (9/12), with three partial responses (25%). All patients with clinical responses also had DNAJ-PKAc specific T cell responses, from which we identified multiple class II-restricted T cell receptors (TCRs) with specificity for DNAJ-PKAc. Correlates of response included both functional neoantigen reactivity and changes in TCR repertoire features over time. Immune escape in two patients corresponded with immune exhaustion rather than neoantigen escape or HLA loss.

  Study phs003970

• Dynamics of checkpoint receptors in γδ T cell subsets are associated with clinical responses during anti-PD-1 immunotherapies

  Gamma delta (γδ) T cells are innate-like lymphocytes with potent anti-tumor properties. Herein, we show that immune checkpoint receptors (ICRs) display differential expression and regulation by the JAK-STAT pathway in Vδ1 and Vδ2 cells and identify constitutive (e.g. TIGIT, PD-1) and inducible (e.g. TIM-3, LAG-3, CTLA-4) ICRs. In melanoma, all γδ T cell subsets downregulated AP-1 transcription factors, but Vδ1 cells specifically expressed high levels of ICR, TOX and inhibitory killer Ig-like receptor (KIR) transcripts, reminiscent of exhaustion. However, patient-derived cells were functionally competent, although induction of LAG-3 and CTLA-4 was impaired. During anti-PD-1 monotherapy, Vδ1 cells specifically bound high levels of therapeutic antibody but only in patients who responded to treatment, revealing a potential new prognostic marker for evaluating the efficacy of IC blockade (ICB) therapy. Finally, expression of KIR genes in Vδ1 cells was downregulated in response to successful ICB therapy. Collectively, our data indicate an intricate relationship between ICRs and γδ T cells and reveal novel approaches by which these cells can be harnessed in order to discern or improve cancer immunotherapy.

  Study EGAS50000001270

• Distinct portrayal of lesions in synchronous multifocal lung adenocarcinoma revealed by genome sequencing

  Distinguishing multiple primary lung cancers in the synchronous multifocal intrapulmonary lesions has important significance on clinical staging and therapeutic decision. To investigate genomic aberration profiles, we applied whole genome and whole exome sequencing, and microarray-based comparative genomic hybridization on 15 intrapulmonary tumors derived from six patients with synchronous multifocal lung cancers having similar histological diagnosis. Any pair of intrapulmonary tumors in a single patient, which shared the identical genetic background and environment, showed an extinctive heterogeneity between each other. Phylogenetic relationship analysis indicated an independently branched evolution among all the tumors, suggesting they were multiple primary lung cancers. EGFR or KRAS mutations were found in 7 or 3 out of the 15 tumors, from 3 or 2 patients, respectively. Somatic mutational heterogeneity of these two genes in a single patient was also observed. Our analysis indicates genomic aberration profiling is valuable for identification of multiple primary lung cancer, especially when high histopathological concordance was observed between lesions. We also suggest a thoroughly molecular diagnosis against therapeutic target genes should be taken for each accessible nodule before making a plan for adjuvant therapy.

  Study EGAS00001001572

• SmMIP-tools:a computational toolset for processing and analysis of single-molecule molecular inversion probes derived data

  Single-molecule molecular inversion probes (smMIPs) provides a modular and cost-effective platform for high-multiplex targeted next-generation sequencing (NGS). Nevertheless, translating the raw smMIP-derived sequencing data into accurate and meaningful information currently requires proficient computational skills and a large amount of computational work, prohibiting wide-scale adoption of smMIP-based technologies. To enable easy, efficient, and accurate interrogation of smMIP-derived data, we developed SmMIP-tools, a computational toolset that combines the critical analytic steps for smMIP data interpretation into a single computational pipeline. Here, we describe in detail two major components of the software. The first is a read processing tool that performs quality control steps, generates read-smMIP linkages and retrieves molecular tags. The second is an error-aware variant caller capable of detecting single nucleotide variants (SNVs) and short insertions and deletions (indels). Using a cell-line DNA dilution series and a cohort of blood cancer patients, we benchmarked SmMIP-tools and evaluated its performance against clinical sequencing reports. We anticipate that SmMIP-tools will increase accessibility to smMIP-technology, enabling cost-effective genetic research to push personalized medicine forward.

  Study EGAS00001005359

• The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space

  Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

  Study EGAS00001002538

• Comprehensive characterization of cell-free tumor DNA in plasma and urine of patients with renal tumors

  Cell-free tumour-derived DNA (ctDNA) allows non-invasive monitoring of various cancers but its utility in renal cell cancer (RCC) has not been well established. A combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n=90) with various renal tumour subtypes, were used to determine ctDNA content in plasma and urine. Our data revealed lower plasma ctDNA levels in RCC relative to other cancers, with untargeted detection of ~33% for both cohorts. A highly sensitive personalised approach, applied to plasma and urine from select patients (n=22), improved detection to ~50%, including in patients with early stage and even benign lesions. A machine-learning based model, applied to untargeted data, predicted this detection, potentially offering a means of triaging patient samples for personalised analysis. We observed that plasma, and for the first time, urine ctDNA may better represent tumour heterogeneity than a single tissue biopsy. Longitudinal sampling of >200 plasma samples revealed that ctDNA can track disease course. These data highlight low ctDNA levels in RCC but indicate potential clinical utility provided improvement in isolation and detection approaches.

  Study EGAS00001003530

• Whole genome sequencing of Ewings Sarcoma

  Sarcomas are cancers of the bone and soft tissue often defined by their gene fusions. However, the timing, context, and processes by which these pathogenic fusions arise are unknown. We explored this in Ewing sarcoma, a cancer driven by EWSR1-ETS fusions, with very few cooperating mutations. Combining whole-genome sequencing with enhanced informatics, we found that the EWSR1-ETS fusion arose from striking rearrangement clusters in 42% of cases (52/124). Notably, these were organized in loops that universally contained the fusion at their center, while also weaving up to 18 genes together with it. We found the same pattern of rearrangements in three additional types of sarcoma. From these data, we define a new signature for sarcoma fusions that precedes other somatic changes, in the earliest replicating DNA of the genome. This dramatic, sudden process impinges on many genes – generating multiple coding changes that profoundly affect the transcriptome, with the disease-defining gene fusion at its core. These rearrangement loops emerge in an early ES clone from which both the primary tumor and the lethal relapse emerged, and then evolved in parallel until clinically detected.

  Study EGAS00001003385

• Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers

  Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor-reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor-reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer – two tumor types for which T cell infiltrates form a positive prognostic marker. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two out of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.

  Study EGAS00001003119

• Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour

  Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.

  Study EGAS00001001836

• SS18-SSX-mediated hijacking of BAF complexes drives synovial sarcoma

  Synovial sarcoma (SS) is defined by a recurrent t(x;18) chromosomal translocation, which produces the hallmark SS18-SSX oncogenic fusion. Incorporation of SS18-SSX into BAF complexes renders BAF complexes aberrant in two distinct manners: the addition of 78aa of SSX onto SS18, and concomitant loss of BAF47 assembly. However, the importance and functional contributions of each of these perturbations on BAF complex targeting and gene expression regulation remain unclear. Here we use an integrative set of genomic approaches in human cancer cell lines and primary tumor samples to define the mechanistic consequences of the SS18-SSX fusion oncoprotein. We find that SS18-SSX hijacks BAF complexes to broad polycomb domains to activate bivalent genes, driving a unique gene expression program distinct from other loss-of-function BAF complex malignancies. Importantly, restoration of BAF47 rescues enhancer activation but is dispensable for proliferative arrest in cell lines. These results demonstrate that gain-of-function SS18-SSX-mediated BAF complex targeting and gene activation is the driving event in SS, and present a mechanism by which distinct functions of BAF complexes can be co-opted to drive oncogenesis.

  Study EGAS00001002920

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001005784

• Target gene sequencing for human normal endometrial glands

  To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we conducted target sequencing of 112 genes for 1,298 endometrial glands and matched blood samples from 36 women. By collecting endometrial glands from different parts of the endometrium, we showed that multiple glands with the same somatic mutations occupied substantial areas of the endometrium. The 112 genes are as follows: ABCC1, ACRC, ANK3, ARHGAP35, ARID1A, ARID5B, ATCAY, ATM, ATR, BARD1, BCOR, BRCA1, BRCA2, BRD4, BRIP1, CAMTA1, CDC23, CDYL, CFAP54, CHD4, CHEK1, CHEK2, CTCF, CTNNB1, CUX1, DGKA, DISP2, DYNC2H1, EMSY, FAAP24, FAM135B, FAM175A, FAM65C, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FAT1, FAT3, FBN2, FBXW7, FGFR2, FRG1, GPR50, HEATR1, HIST1H4B, HNRNPCL1, HOOK3, KIAA1109, KIF26A, KMT2B, KMT2C, KRAS, LAMA2, LRP1B, MLH1, MON2, MRE11A, MSH2, MSH6, MTOR, NBN, PALB2, PHEX, PIK3CA, PIK3R1, PLXNB2, PLXND1, PMS2, POLE, POLR3B, PPP2R1A, PTEN, PTPN13, RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD52, RAD54B, RAD54L, RICTOR, SACS, SIGLEC9, SLC19A1, SLX4, SPEG, STT3A, TAF1, TAF2, TAS2R31, TFAP2C, TNC, TONSL, TP53, TTC6, UBA7, VNN1, WT1, XIRP2, ZBED6, ZC3H13, ZFHX3, ZFHX4, ZMYM4.

  Study EGAS00001005914

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001006306

• Phosphoproteomics adds value to treatment recommendations in molecular tumor boards

  Precision oncology approaches employing genomics-guided targeted therapies for individual patients have provided significant survival benefits in several cancer types. However, low response rates in most solid malignancies, many patients without actionable genomic lesions, and increasing evidence that non-genomic mechanisms may play an important role in tumors indicate that genomics alone is often insufficient to inform and guide the clinical care of patients. Here, we show for the first time that comprehensive (phospho)proteome profiling is feasible and informative in a real-world prospective precision oncology setting. We developed a novel tumor pathway activity (TUPAC) scoring methodology that provides a holistic perspective on dysregulated receptor tyrosine kinase (RTK) signaling in individual patients. Based on 919 tumor tissue profiles of patients enrolled in the national NCT/DKTK MASTER study and the INFORM registry trial, we illustrate how TUPAC scoring can be used to uncover individual tumor biology in rare cancers and demonstrate that TUPAC methodology identifies EGFR-driven sarcomas despite the absence of genetic EGFR alterations. Overall, our work demonstrates the utility of the additional phosphoproteome data layer to enhance therapeutic recommendations in molecular tumor boards.

  Study EGAS00001007891

• IFN-γ and TNF-α drive a CXCL10+ CCL2+ Macrophage Phenotype Expanded in Severe COVID-19 Lungs and Inflammatory Diseases with Tissue Inflammation

  We explored how the human macrophages response to different inflammatory factors, focusing particularly on the effects of antiviral interferons (IFN-β and IFN-γ), pro-inflammatory cytokines such as TNF-α, and other mediators like IL-4. Co-cultured fibroblasts were a component in some conditions to generate factors produced by resident stroma. We used a single-cell antibody-based hashing strategy to multiplex samples from different stimulatory conditions in one sequencing run. This macrophage transcriptomic data reveals distinct macrophage activation states and polarizations shaped by different tissue-related inflammatory conditions at single-cell resolution. We further performed an unbiased integration between tissue-level macrophages and this stimulated human blood-derived macrophages, which pinpoint an IFN-γ and TNF-α synergistically driven inflammatory macrophage phenotype expanded in severe COVID-19 lungs and other inflamed disease tissues.

  Study phs002780

• A Multimodal Atlas of Human Brain Cell Types

  "A multimodal atlas of human brain cell types" includes sample data targeting two cell types that show species differences between mouse and human. First, it includes a detailed transcriptomic, morphological, and electrophysiological characterization of cell types in layer 1 of human middle temporal gyrus, focusing primarily on different inhibitory cell types. This project also includes gene expression data collected from nuclei in layer 5 of human fronto-insula, with a goal of identifying transcriptomic signatures of Von Economo neurons. Control samples collected as part of the same experiment are also included in the data set. This study was conducted as part of a collaboration between the Allen Institute for Brain Science, the University of Szeged, and the J. Craig Venter Institute. Collaborators request that publications resulting from these data cite their original publication: Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type (PMID: 30150662).

  Study phs001791

• DNA and RNA sequencing of single human haploid germ cells

  Our goal was to look at allele-specific gene expression in single spermatids from two human donors. We first genotyped and phased each donor using a combination of linked-read sequencing (one sample per donor, 10X Chromium), and single haploid whole genome sequencing (53 spermatids for the first donor, and 19 for the second). We then sequenced mRNA from single spermatids (302 from the first donor, and 164 from the second), using the Smart-Seq2 protocol. We used these gene expression data, in combination with the haplotype data, to look for gene products that exhibit allele-specific bias reflecting the haploid genotype of the cell. We find a large class of human genes that show such allele-specific bias in spermatids, indicating that these gene products are not fully shared across the cytoplasmic bridges that connect spermatids. We term these genes “genoinformative markers” (GIMs).

  Study phs002279

• Whole genome sequencing data from tumor and normal samples

  Whole genome sequencing FASTQ files from tumor and normal samples from 202 patients. All experiments reported in this article were performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified and College of American Pathologists (CAP)-accredited laboratories at Personalis Inc., as guided by the Association for Molecular Pathology (AMP) and CAP’s joint recommendations52. Preferred input material consisting of FFPE slides (enabling H&E and macrodissection which is part of the standard NeXT Personal process) was not available for the majority (94%) of tumor samples. Most tumor samples (72%) were processed from FFPE curls, with the remaining processed from pre-extracted DNA and fresh frozen material. Where FFPE material on slide was available, tumor sections were macrodissected to increase tumor content, with a minimum allowable cellularity threshold of 20% determined by pathological review. The tumor cellularity threshold of 20% was chosen based on prior work demonstrating that no significant correlation is observed between tumor purity and assay limit of detection (LOD) at this threshold31. Genomic DNA was isolated from tumor and normal samples and WGS libraries prepared as previously described31. Genomic DNA was isolated from matched tumor and normal samples using the Qiagen AllPrep DNA/RNA FFPE Tissue Kit or the QIAamp DNA Mini Kit (QIAGEN, Germantown, MD, USA) using internally optimized workflows. WGS sequencing libraries were prepared with 120-500 ng of acoustically sheared genomic DNA (Covaris LLC, Woburn, MA, USA) using the KAPA HyperPrep Kit (Roche Sequencing Solutions, Pleasanton, CA, USA) and customized methods. Libraries were cleaned-up using AMPure XP beads and then quantified using the KAPA Library Quantification Kit (Roche Sequencing Solutions, Pleasanton, CA, USA), before being sequenced to 30X depth of coverage using a NovaSeq 6000 instrument (Illumina, San Diego, CA, USA).

  Dataset EGAD50000001909

• Anaplastic oligodendroglioma exome and RNA sequencing data

  Anaplastic oligodendrogliomas (AOs) are rare primary brain tumors which are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosome 1p/19q co-deletion and IDH mutation. We analyzed 51 AOs by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. 80% of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frame shift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumor type. Our analysis provides further insights into the unique and shared pathways driving AO.

  Study EGAS00001001209

• RNA sequencing CYLD cutaneous syndrome

  Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. Novel recurrent mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumours suggest that isoform specific DNMT3A2 mutations are associated with dysregulated Wnt/ß-catenin pathway signaling. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumours. These findings add novel dimensions to existing paradigms of cutaneous tumorigenesis and metastasis.

  Study EGAS00001003841

• RNAseq of whole blood in 359 idiopathic pulmonary arterial hypertension patients reveals biological heterogeneity

  Patients with idiopathic, heritable, or drug-induced pulmonary arterial hypertension (referred to throughout as PAH) were recruited from expert centers across the UK as part of the PAH Cohort study (www.ipahcohort.com). In each case, diagnosis was confirmed by right heart catheterization following established international guidelines, which remained unchanged for the duration of this study. Healthy volunteers were recruited at the same centers and samples processed using the same standard operating procedure at all sites. All individuals gave written, informed consent with local ethical committee approval. Whole blood (3 ml) was collected in Tempus Blood RNA Tubes, and RNAseq was performed using established Illumina methodologies (see online supplement for further details).

  Dataset EGAD00001007981

• 13 WGS and 8 TCS data of ENKL patients treated with pembrolizumab.

  Whole-genome sequencing (WGS) was performed for 13 pairs of tumor-normal samples from patients diagnosed with NKTL. Genomic DNA from tumor tissue was extracted with QIAamp DNA Mini Kit. The DNA for the matching normal was obtained from blood or buccal swabs and purified by Blood and Cell Culture DNA Mini kit or E.Z.N.A. Tissue DNA Kit (Omega Bio-tek) according to manufacturer’s instructions. The quantity and quality were assessed by Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen) and agarose gel electrophoresis. All sequencing libraries were prepared using TruSeq Nano DNA Library Prep Kit (Illumina). Paired-end sequencing was performed on Illumina HiSeq 2000 or HiSeq X Ten as 2x101 bp or 2x151 bp, respectively. 8 NKTL FFPE specimens were screened for somatic mutations using deep targeted capture sequencing (TCS). FFPE rolls or slides were extracted using QIAamp DNA FFPE Tissue kit (QIAGEN). The FFPE genomic DNA was treated with NEBNext FFPE DNA Repair Mix and assessed by Quant-it PicoGreen dsDNA Assay Kit (Invitrogen). The library was generated from 10-200 ng DNA with SureSelectXT Low Input Target Enrichment System for Illumina Paired-End Sequencing Library (Agilent Technologies) according to manufacturer’s instructions. RNA based probe was designed with SureDesign (Agilent Technologies) to target-capture 140 genes. Next, the captured libraries were pooled in equimolar concentration and sequenced on Illumina Novaseq 6000 platform with SP or S1 chip. Reads aligning to 40 selected genes were isolated post-alignment for this submission. Prefix used in filenames: T - Tumor samples N - Matched-Normal samples

  Dataset EGAD00001004140

• Functional Significance of Prostate Cancer Risk-SNPs

  Prostate Cancer (PrCa), the most frequently diagnosed solid tumor in men in the U.S., results in ~192,000 new cases and ~27,000 deaths per year. Although the variation of PrCa incidence is likely to be the result of several factors, there is a large body of literature that strongly implicates a genetic etiology. Genome-wide association studies (GWAS) have emerged as the most widely used contemporary approach to identify genetic variants (in particular SNPs) that are associated with increased risk of human disease. For PrCa, at least five GWAS have now been performed yielding a substantial number of well-validated SNPs that are associated with an increased risk of PrCa, and that number continues to grow. A significant problem for many of the PrCa risk-SNPs identified so far, however, is that they do not lie within or near a known gene and they have no obvious functional properties. These findings suggest that many (if not most) of these risk-SNPs will be located in regulatory regions that control gene expression rather than in coding regions that may directly affect protein function. Therefore, in order to define the functional role of currently known risk-SNPs, the target genes must first be identified. A promising strategy to address this problem involves the use of expression quantitative trait loci (eQTL) analysis. Unfortunately, most of the publically available SNP-Transcript eQTL datasets utilize lymphoblastoid cells with only a handful using tissue from target organs. Although useful, these datasets alone are unlikely to be sufficient. Recent studies have demonstrated that gene expression and gene regulation occur in both a tissue-specific and tissue independent fashion and suggest that a complete repertoire of regulatory SNPs can only be uncovered in the context of cell type specificity. To date, such a tissue-specific dataset for normal prostate tissue does not exist. In this study, we have constructed a normal prostate tissue specific eQTL data set.

  Study phs000985

• After the completion of CINECA, EUCANCan, and euCanSHare. What's next?

  CINECA, EUCANCan, and euCanSHare were part of the EUCAN Cluster, made up of six projects that received funding under the same Horizon 2020 call. All EUCAN projects (CINECA, EUCANCan, EUCAN-Connect, euCanSHare, Receptor Plus, and ReCoDID) were aimed at facilitating data reuse and knowledge discovery by enhancing data exchange and long-term collaboration in the health field. Here are some highlights about EGA’s contribution to these projects. CINECA: advances in Federated discovery and infrastructure for cohorts CINECA (Common Infrastructure for National Cohorts in Europe, Canada, and Africa) developed a federated cloud-based infrastructure for making genomic and biomolecular data accessible. The project has assembled a virtual cohort of 1.4 million individuals from sources such as the EGA, CanDIG and H3Africa. The EGA–CRG co-leaded a work package Work Package 1 on Federated Data Discovery and Querying. Beacon v2, championed by Jordi Rambla and Lauren Fromont, has been one of the central elements for the discovery of human genetic and phenotypic data. The EGA-CRG contributed to the development of a model for cohort discovery inside the Beacon v2 model. The team also delivered a Discovery Portal was implemented to explore cohorts and individuals of synthetic data. It is a UI that gathers a network of Beacons, a service for query expansion, and a visualisation tool. Have a look at the Discovery Portal UI, gathering a network of Beacons. You will find entities such as the Barcelona Supercomputing Center (BSC), BioData.pt and the European Genomic Data Infrastructure (GDI), among others. euCanSHare: facilitation of data access management This joint EU-Canada project aimed to build a European and Canadian FAIR platform for cardiovascular data sharing and analysis. The EGA’s tasks contributed to the development of the data management plan and data flows, main web-portal and interoperability protocols. An important part of the EuCanShare platform is the data access manager, a tool for the data owners to control the access to their sensitive datasets. We built a user-friendly interface for data access committees (data owners) to easily manage their data requests and access credentials. The data access portal facilitates the creation and internal organization of the data access committees as well as the linkage of data usage conditions to specific datasets. The interface includes filters for browsing requests and page to visualize the request history helping with the handling of data access requests. EUCANCan: toward a federation of clinical institutions in oncology The EUropean-CAnadian CANcer Network worked towards building a federated network to advance personalized medicine in oncology, by promoting the standard analysis, management and sharing of harmonized genomic and phenotypic data. The EGA led tasks on defining data flows and preparing an adapted infrastructure for long-term data storage and sharing. One of the key contributions was the conception of the EGA communities, offering standard and interoperable solutions for data discovery, processing, and sharing to projects and institutions that would like to manage and share data in the context of the EGA ecosystem. What's Next? The participation in projects such as CINECA, EUCANCan, and euCanSHare provide us with experience for future projects. We are happy to enhance data sharing and reuse, vital for advancing clinical and genomic research. The Discovery Portal is a wonderful proof of concept for the Beacon network. Next, we will finalise both the network and the user interface, and make sure it can be applied to more clinically-centred settings like hospitals. Most data hosted at the EGA are about cancer research. Currently, we contribute to building tools and infrastructure to empower oncology research in several European projects such as EUCAIM, EUCANIMAGE and EOSC4Cancer. We also do not lose sight of initiatives in the field such as the International Cancer Genome Consortium (ICGC) with the project ARGO, whose data model was adopted in EUCanCan.

  Blog cineca-eucancan-and-eucanshare-were-concluded-in-june

• Whole genome analyses of the childhood cancer neuroblastoma

  Neuroblastomas are tumors of peripheral sympathetic neurons and are the most common solid tumor in children. To determine the genetic basis for neuroblastoma we performed whole-genome sequencing (6 cases), exome sequencing (16 cases), genome-wide rearrangement analyses (32 cases), and targeted analyses of specific genomic loci (40 cases) using massively parallel sequencing. On average each tumor had 19 somatic alterations in coding genes (range, 3-70). Among genes not previously known to be involved in neuroblastoma, chromosomal deletions and sequence alterations of chromatin remodeling genes, ARID1A and ARID1B, were identified in 8 of 71 tumors (11%) and were associated with early treatment failure and decreased survival. Using tumor-specific structural alterations, we developed an approach to identify rearranged DNA fragments in sera, providing personalized biomarkers for minimal residual disease detection and monitoring. These results highlight dysregulation of chromatin remodeling in pediatric tumorigenesis and provide new approaches for the management of neuroblastoma patients.

  Dataset EGAD00001000282

• The chemotherapeutic CX-5461 is extremely mutagenic and may increase cancer risk

  The chemotherapeutic agent CX-5461 or pidnarulex has been fast-tracked by the US FDA for treatment of BRCA1-, BRCA2-, and PALB2-mutated cancers. It is under investigation in Phase I/II clinical trials. Here we find that although CX-5461 exhibits synthetic lethality in BRCA1-/BRCA2-deficient cells, it also causes extensive, non-selective, collateral mutagenesis in all cells, to magnitudes that exceed known environmental carcinogens, raising public health concerns regarding its potential for promoting secondary cancers.

  Study EGAS50000000023

• Ballett

  TSO500 study: The project, called "BALLETT" (Belgian Approach of Local Laboratory Extensive Tumor Testing), has a double goal: (1) show the relevance of broad molecular profiling to improve oncological patients care, (2) demonstrate that broad molecular testing can be performed in a decentralized setting by local diagnostics laboratories in a fully standardized and uniform way while complying with the highest quality standards. NCT05058937 The publication number is: Your manuscript ID is bcr-2023-256124. Title: CUP and BRAF V600E meeting the BEACON combination.

  Study EGAS50000000478

• Testicular large B-cell lymphoma is genetically similar to PCNSL and distinct from nodal DLBCL

  Next generation sequencing (NGS) data analyzed in Rivas-Delgado, López, et al. HemaSphere 2024. Single nucleotide variants (SNVs) and short insertions /deletions (indels) were evaluated in 42 samples using a B-cell malignancy-oriented targeted panel covering 115 genes (SureSelectXT, Agilent Technologies and sequenced in a MiSeq instrument (Illumina; 2x150bp; mean coverage of 599x). The NGS data of 39 samples is provided here. The 3 additional samples were previously published. Please, see the original publication for additional details.

  Study EGAS50000000521

• BE_screens_of_WRN_gene_in_MSI_models

  We will take advantage of a base-editing screening strategy to engineer mutations in the WRN gene by deep mutagenesis. Two MSI-H cell lines sensitive to WRNi will be genetically modified to express doxycycline-inducible ABE and CBE base editors through a knock-in strategy. Moreover, we will design a pooled library of ~4000 gRNAs targeting the WRN gene plus appropriate controls gRNAs. Library-transduced cells will be selected with WRNi to identify WRN mutations able to interfere with the activity of WRNi.

  Study EGAS00001006872

• Expression quantitative trait loci influence DNA damage-induced apoptosis in cancer

  The analysis of e2QTL allows for the identification of context-specific eQTL effects (Kim-Hellmuth et al. (2017), PMID: 28814792). To evaluate how inter-individual genetic variability influences the regulation of DNA damage-induced apoptosis, we performed e2QTL analysis of CD8+ T cells from 461 healthy European participants stimulated with high doses of 5 different carcinogens. These include Methyl-methanesulfonate (MMS), tert-butyl-hydroperoxide (TBOOH), benzo(a)pyrene-7,8-diol-9,10-epoxide (BPDE), 4-hydroxycyclophosphamide (HC) and UVC radiation.

  Study EGAS50000000666

• Childhood Cancer Data Initiative (CCDI): CCDI Pediatric In Vivo Testing Program - Leukemia

  The goal of this study is to molecularly characterize a large panel of pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) previously established in immune-deficient mice. These PDXs are utilized as part of the NCI-funded Pediatric Preclinical In vivo Testing (PIVOT) program to identify novel agents and combinations. Biospecimen data include next-generation sequencing (RNAseq, whole exome sequencing, DNA copy number variation), whole-genome analysis of cytogenetic abnormalities, and DNA fingerprint for quality control.

  Study phs003164

• Molecular biomarkers in progression from refractory celiac disease to the lethal cancer variety enteropathy associated T cell lymphoma (EATL)

  Enteropathy associated T cell lymphoma (EATL) is frequently preceded by a state of refractoriness to the gluten-free diet, called “refractory celiac disease” or RCD. We aim to study which mutations and copy number aberrations are already manifest in RCD and to identify differences between RCD patients that do, and do not, develop EATL. We have applied whole exome sequencing to detect mutations and copy number aberration predictive for progression from RCD to EATL.

  Study EGAS00001006669

• Childhood Cancer Data Initiative (CCDI): Pediatric In Vivo Testing Program – Sarcomas and other Solid Tumors

  The primary goal of this project involves the comprehensive molecular profiling of patient-derived xenograft (PDX) mouse tumor models. Molecular profiling of each PDX model will include whole exome sequencing (WES), RNAseq, MethylEPIC arrays, CytoSNP array, and DNA fingerprint for quality control. Limited clinical demographic data (e.g. diagnosis, disease site, disease status) will be obtained. This data can be utilized to validate PDX models with matched patient tumors and can be used to guide model selection for downstream preclinical drug testing.

  Study phs003161

• Application of targeted long-read methylation sequencing to dissected lung cancer tissues

  To investigate DNA methylation patterns within the tumor microenvironment, multiple regions were dissected from fresh-frozen sections of two lung adenocarcinoma specimens using the Millisect system. These regions were annotated based on spatial transcriptome data. DNA samples extracted from these regions were subjected to targeted long-read methylation sequencing using t-nanoEM. To establish a control dataset, short-read whole-genome sequencing (WGS) was performed on the tumor and normal parts, and long-read WGS was performed on the tumor part.

  Study JGAS000757

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001889

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001891

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001892

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001893

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001894

• DEPArray-based sorting of pure carcinoma and stromal populations from formalin-fixed paraffin-embedded (FFPE) tissues followed by shallow whole genome sequencing

  To overcome the challenges of low DNA yields, degraded DNA by formalin fixation and diluted signal of genomic aberrations by non-carcinoma components in the heterogeneous FFPE samples, we isolated pure carcinoma and stromal cells using the DEPArray™ NxT system, a microchip-based digital sorter that allows isolation of pure, homogeneous subpopulations of cells from FFPE samples. We isolated pure carcinoma and stromal cell populations from 12 FFPE tissues, including tissues from 9 primary and metastatic breast cancer and 3 primary ovarian high-grade serous carcinomas. This was followed by downstream shallow whole genome sequencing (WGS) for copy number landscape profiling for 10 samples. Seven out of 10 samples (even some with low tumour content or of old age) produced good quality genomic data, detecting sCNA in all carcinoma population samples but not in the stromal populations.

  Dataset EGAD50000001895

• Catalogue Statistics

  EGA Statistics Bibliography Growth Community Archive Distribution Catalogue What is in the EGA? The European Genome-phenome Archive (EGA) overview The EGA archives and distributes the results of several types of studies. Such studies include genome-wide association studies (GWAS), different purpose sequencing and molecular diagnosis assays among others. Moreover, these studies target many different kind of diseases from cancer to neurodegenerative alterations. We summarised all this data in the charts below. The statistics are computed daily based on an updated list of studies. Each pie chart depicts a different aspect of the studies: which disease type was studied, which type of sampling method was used and what was the scope of the genomic analysis. Number of studies per disease type Studies in the EGA by disease barHorizontalChart('disease-graph', 'https://stats.ega-archive.org/catalog/by_disease') Number of studies per technology type Studies in the EGA by technology barHorizontalChart('technology-graph', '/stats/studies/technology', 'Include dbGaP') Number of studies per sample type Studies in the EGA by samples barChart('samples-graph', '/stats/studies/sample-types', 'Include dbGaP')

  Documentation about/statistics/catalogue

• Chromosomal instability shapes the tumor microenvironment of oesophageal adenocarcinoma via a cGAS–chemokine–myeloid axis

  This study employed whole-genome sequencing (WGS) to investigate genomic alterations in oesophagogastric adenocarcinoma, with a focus on mechanisms of chromosomal instability. Twelve tumour samples were analysed, including specimens obtained prior to neoadjuvant chemotherapy and at surgical resection. WGS was used to identify structural variants, quantify tumour mutational burden, and detect potential driver mutations across samples. The study aimed to correlate genomic measures of chromosomal instability with clinicopathological features to improve understanding of tumour biology.

  Study EGAS50000001561

• RNAseq___Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000813

• Discovery_of_resistance_mechanisms_to_the_BRAF_inhibitor_vemurafenib_in_metastatic_BRAF_mutant_melanoma

  We propose to biopsy 20 consented BRAF mutant melanoma patients at Addenbrooke's Hospital pre-treatment with vemurafenib and also upon the development of resistant disease, with the aim of using exome sequence and SNP6 data to identify novel sequence variants and copy number alterations that can be used to validate observed resistance mechanisms in our cell line models and also to use these models to inform as to likely candidate small molecule inhibitors to overcome resistance and that could be tested in the clinical trial setting.

  Study EGAS00001000812

• Amplicon_based_sequencing_of_drug_resistant_organoids

  A BRAF V600E colorectal organoid which is sensitive to MAP kinase inhibition was mutagenised with the chemical mutagen ENU and then drug selected using a combination of Trametinib, Dabrafenib and Cetuximab. Single cell derived organoids were then manually picked and expanded in drug. Resistance was confirmed in a 14 day assay and DNA was collected. These then underwent targeted amplicon-based sequencing to confirm candidate resistance effectors from a screen in 2 2D BRAF V600E colorectal cell lines. Pools of resistant clones were also sequenced.

  Study EGAS00001001639

• ENU_LS_411N_TripleTherapy

  BRAF V600E colorectal cancers do not respond to the only currently FDA approved targeted therapy for CRC. There is currently a trial underway in the UK recruiting V600E CRC patients for treatment with a triple therapy combination of Cetuximab, Trametinib and Dabrafenib. We have mutagenized a pool of V600E CRC cell lines and treated with this triple therapy to select out drug resistant clones. We will now sequence these drug resistant clones with the aim of identifying common point mutations engendering resistance to this new therapy.

  Study EGAS00001001777

• The WID-CIN test identifies women with, and at risk of, cervical intraepithelial neoplasia grade 3 and invasive cervical cancer (CIN3+)

  We analysed DNA methylation at >850,000 CpG sites across the genome using the Illumina EPIC array in a total of 1,254 cervical liquid-based cytology samples from cases of screen-detected histologically verified CIN1-3+ (98% hrHPV-positive) and population-based control women free from any cervical disease (100% hrHPV-positive). We developed the WID-CIN-test which is a DNA methylation signature consisting of 5,000 CpG sites.

  Study EGAS00001005078

• Mutational_burden_in_human_hair_follicles

  We would like to dissect human hair follicles and assess the mutations found in diffferent parts of the follicle eg bulge, root etc. We can also compare this with mutations found in the surrounding epidermis of the same patients (this is done under a different study). This may provide insights into the origin of PTCH1 mutants frequently seen in basal cell carcinoma but so far not located in our whole epidermis work as well as defining the clonality of the hair follicle

  Study EGAS00001004462

• Transcriptomic predictors of survival for palbociclib + endocrine therapy vs. capecitabine in aromatase inhibitor-resistant breast cancer from GEICAM/2013-02 PEARL

  We examined transcriptomic tumor features associated with survival from GEICAM/2013-02 PEARL, a phase III trial of palbociclib + ET vs. capecitabine in aromatase inhibitor-resistant HR+/HER2- MBC. PAM50 intrinsic subtype predicted PFS differences between palbociclib + ET and capecitabine, and lower B-cell-associated gene expression predicted longer OS with palbociclib + ET vs. capecitabine. These features may help identify HR+/HER2- tumors resistant to further ET-based treatment with CDK4/6 inhibitors.

  Study EGAS00001008177