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• Targeted sequencing of brain AVM tissues

  We previously identified somatic activating KRAS mutations in a majority of human arteriovenous malformations (AVMs), using whole exome sequencing. We have now performed targeted sequencing on AVMS, investigating genes in the RAS-MAPK pathway, angiogenesis and brain vascular disorders among others.

  Study EGAS00001006729

• ExHiBITT shows that microbiome from colon biopsies, caecal fluid from colonoscopies and faecal samples shape different microbiome-host interactions

  The objective of the colonoscopy study is to carry out the 16s sequencing of colon biopsies and faecal samples provided in ExHiBITT study to compare potential fluctuations in the microbiota of different sites.

  Study EGAS00001007313

• Phenotype data for clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. This dataset includes clinical phenotype data.

  Dataset EGAD00001006200

• FIT interval CRCs versus Screen-detected CRCs

  Formalin-fixed, paraffin-embedded samples from 27 FIT interval CRC and 54 screen-detected CRCs collected in a pilot-program of FIT-based CRC screening in the southwest and northwest regions in the Netherlands, were used in this study. DNA was extracted for 1) Shallow Sequencing (copy number analysis) and 2) TSACP Amplicon Cancer Gene Panel (mutations) of 22 FIT Interval CRCs and 45 screen-detected CRCs.

  Dataset EGAD00001006409

• Whole genome sequencing of Xeroderma Pigmentosum leukemias samples

  In the current study we report for the first time the unique collection of 6 leukemias and two sarcomas from XP-C. Comprehensive WGS-based mutational analysis provides genetic explanation for the increased incidence of leukemia in XP-C and describes an unique mutational process in internal tumors associated with NER deficiency. Raw data are provided in FASTQ format and variant analysis as VCF files.

  Dataset EGAD00001006322

• Genotype data for clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial

  ABACUS is a single arm phase 2 study that investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in 95 patients with muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. This dataset includes the processed data from FMOne.

  Dataset EGAD00001006201

• RNAseq of 76 samples from Uveal Melanoma tumors

  Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss.

  Dataset EGAD00001004398

• Reproducibility of variant calls in replicate next generation sequencing experiments

  To examined the reproducibility of nucleotide variant calls in replicate sequencing experiments of the same genomic DNA, we performed targeted sequencing of all known human protein kinase genes (kinome) (~3.3 Mb) using the SOLiD v4 platform. This data set contains 17 breast cancer samples that were sequenced in duplicate (n=14) or triplicate (n=3), in order to assess concordance of all calls and single nucleotide variant (SNV) calls.

  Dataset EGAD00001001209

• RNA sequencing of cytokine-induced T cell responses

  Cytokines affect T cell responses by polarising them to different phenotypes. We isolated T cells from healthy platelet donors and cultured them in resting and stimulated conditions, as well as in the presence of Th1, Th2, Th17 and iTreg cocktail. In addition, T cells were stimulated in the presence of IL-10, IL-21, IL-27, IFNb and TNFa. We performed bulk RNA sequencing to assess impact of different disease-relevant cytokines upon T cell response.

  Dataset EGAD00001005291

• Sensitive and reproducible cell-free methylome quantification with synthetic spike-in controls

  We created three technical replicates of cell-free DNA from AML patient plasma to assess batch effects and utility of spike-in controls for the cfMeDIP-seq method. Each set of samples were given to three different technicians with slightly different protocols. Details can be found in Wilson et al. "Sensitive and reproducible cell-free methylome quantification with synthetic spike-in controls".

  Dataset EGAD00001006986

• scWGS dataset of Characterization of UV DNA damage in B-cell precursor acute lymphoblastic leukemia

  Extensive characterization of mutational signature SBS7a in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) samples. We aimed to describe the presentation of SBS7a in BCP-ALL, identify other pediatric cancers presenting with SBS7a, look into the link of SBS7a and UV-light in the context of BCP-ALL and cancers with provable UV exposure, and pinpoint when SBS7a was acquired.

  Dataset EGAD00001015601

• Deep sequencing of the gut microbiome from 946 healthy donors of the Milieu Intérieur cohort

  In this study, we aim to determine, in a thousand healthy donors, how the profile and dynamics of the gut microbiome are affected by host factors such as sex, age and lifestyle parameters.

  Study EGAS00001004437

• CSER: South-Seq: DNA Sequencing for Newborn Nurseries in the South

  SouthSeq, part of the Clinical Sequencing Evidence-Generating Research (CSER2) effort, aims to perform genome sequencing for infants in nurseries at hospitals in Alabama, Mississippi, Louisiana, and Kentucky. SouthSeq aims to sequence 600 newborn babies presenting with congenital anomalies, or other signs of a rare genetic disorder. The primary goals of SouthSeq are to provide early diagnoses to children with rare genetic conditions, to demonstrate the utility of genome sequencing as a frontline test with potential to improve intermediate and long-term clinical outcomes, and to equip non-genetics providers to deliver test results in order to facilitate the conduction of genome sequencing outside of major medical centers where patients may not have access to a genetics provider. SouthSeq also aims to ensure that genomic testing is applied across diverse communities; recruitment efforts focus on patients from rural and minority populations that have been historically under-represented in both medicine and genomics research. Sequencing and analysis for SouthSeq are being conducted at the HudsonAlpha Institute for Biotechnology in Huntsville, Alabama (https://www.hudsonalpha.org/). Enrollment of infants with signs of genetic disease is approved at five clinical sites, including nurseries at the University of Alabama at Birmingham, the University of Mississippi Medical Center, Woman's Hospital in Baton Rouge, Children's Hospital in New Orleans, and the University of Louisville. Both biological parents are enrolled when available so that follow-up testing can be performed to determine inheritance. Further, participant families may choose to opt-into return of secondary findings identified in the proband, which focus on pathogenic and likely pathogenic variation identified within ACMG SFv3.0 genes.

  Study phs002307

• Mechanism of Action of Vitamin E in NAFLD

  We conducted a single-center prospective mechanistic randomized trial (clinicaltrials.gov NCT01792115). Adult patients with NAFLD were enrolled between May 2013 and November 2016. All patients underwent a 12 weeks run-in period of lifestyle intervention. Following the run-in phase, patients underwent a baseline evaluation including blood tests, glucose tolerance testing, measurement of liver fat content by 1H-magnetic resonance spectroscopy (MRS) and a percutaneous liver biopsy. Patients with no evidence of NAFLD on the entry liver biopsy ended their participation in the study at that point. Patients with histological confirmation of NAFLD (either NAFL or NASH) on the baseline biopsy were randomized at a 1:1:1 ratio to receive one of 3 doses of natural vitamin E (RRR-alpha-tocopherol, Pharmavite), 200, 400 or 800 IU/d, for 24 weeks, and were followed at a 1-8 week intervals in a parallel assigned design. While on vitamin E treatment, patients were encouraged to continue and adhere to the lifestyle and dietary guidelines of the run-in phase. On week 4 of vitamin E treatment, a repeat MRS and liver biopsy were performed. On week 24, a final MRS was performed to assess treatment response. The primary endpoint was the reduction of liver fat content by MRS from baseline (immediately prior to starting vitamin E) to week 24 of treatment, and a response was defined as a relative reduction of ≥25% in liver fat content by MRS between baseline and week 24. Early changes in the hepatic transcriptome were investigated at week 4 comparing non-responders to responder in a nested design.

  Study phs001930

• Systems Analysis of the PfSPZ Vaccine in Kenyan Infants

  The PfSPZ vaccine is a candidate vaccine targeting the Plasmodium falciparum parasite, which is the cause of the most lethal type of human malaria. This study used de-identified blood samples collected from 316 infants aged 5 to 12 months (inclusive) enrolled in a Phase 2, randomized, placebo-controlled trial (NCT02687373) of the PfSPZ malaria vaccine, conducted in a region of western Kenya where malaria transmission is high and perennial. The study began in July, 2016, after peak malaria transmission, and was completed in August, 2018. In this study, three doses of the PfSPZ Vaccine (4.5x105 PfSPZ, 9.0x105 PfSPZ, and 1.8x106 PfSPZ) were tested against a normal saline placebo comparator. In all four groups, doses were administered in 3 doses at 0, 8, and 16 weeks by direct venous inoculation. Vaccine efficacy was determined at 3, 6, and 12 months of follow-up after the third immunization. RNA was extracted from whole blood collected in PAXgene tubes before PfSPZ immunization, and two weeks after the third (final) dose, from 262 children for which sufficient material was available at both time points (82% of 316 enrolled children; 525 samples). RNA was depleted of globin and ribosome transcripts before library generation and sequencing on the Illumina NovaSeq platform. RNA-seq expression data was analyzed to determine blood transcriptional signatures, before and after PfSPZ vaccine immunization, that predicts sterile protection from naturally occurring P. falciparum infection or delayed parasitemia at 3 months post-immunization. Gene expression data will also be correlated to P. falciparum-specific IgG antibody and cellular responses to identify possible molecular correlates of vaccine-induced immunogenicity

  Study phs002196

• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• Correlative Studies for Protocol #14-C-0059: T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Patients with GD2+ Solid Tumors, a Collaboration with CIMAC-CIDC

  This study is a retrospective correlative analysis of immune cell phenotypes in samples from a Phase I clinical trial (NCT02107963) of GD2 CAR-T cells (GD2-CAR.OX40.28.z.iC9) in children and young adults with osteosarcoma and neuroblastoma. The study was a 3+3 dose-escalation study with four dose levels (1 x 10(5) transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg). Apheresis and final manufactured GD2 CAR-T product samples were analyzed by bulk RNA sequencing and ATAC sequencing. The patients were stratified into good CAR-T expanders (peak CAR-T expansion >1000 GD2 CAR copies/100ng DNA) and poor CAR-T expansion (peak CAR-T expansion Increased naïve T cell subsets in baseline apheresis are associated with patients who experienced good CAR T cell expansion A T cell exhaustion signature was observed in the manufactured GD2 CAR-T product and may have contributed to lack of efficacy observed in this trial Increased myeloid-derived suppressor cell (MDSC) signatures were observed in patients with poor CAR-T expansion CAR-T product in good expanders displayed increased AP-1 factor transcription factor motifs, such as BATF, JUN, and FOS Data provided in dbGaP for this study include: Bulk RNA-Seq data for 11 pre-treatment peripheral blood and 11 GD2 CAR-T product from 14 patients. ATAC sequencing of 22 peripheral blood samples and 5 GD2 CAR-T products from 14 patients.

  Study phs003455

• Transcriptional Response to Hypoxia in iPSC-Derived Endothelial Cells from a High Altitude Adapted Population

  We established lymphoblastoid cell lines from 10 adult individuals of Tibetan ancestry living in the Chicago area. These lines were reprogrammed to induced pluripotent stem cells (iPSC). We validated genetic ancestry by genome-wide SNP array genotyping and population genetic analyses. After being subjected to standard quality control testing iPSCs were differentiated into endothelial cells. Following differentiation, endothelial cells were isolated via a pull down protocol using beads coated with an antibody for a canonical surface cell marker of the vascular endothelium (CD144). Purified vascular endothelial cells were cultured in parallel in normoxia (20% O2) and hypoxia (1% O2) for 48 hours prior to harvesting and processing for bulk RNA-sequencing. We provide imputed genotype data and bulk RNA-sequencing data in normoxia and in hypoxia for each of the 10 individuals. We also provide multiplexed scRNA-sequencing data for the 10 Tibetan individuals pooled with 10 CHB individuals from the 1000 Genome Project. Additionally, we provide scRNAseq data for the cardiomyocytes derived from the same iPSC lines from the Tibetan individuals pooled together with cardiomyocytes derived from iPSC lines of 10 CHB individuals from the 1000 Genome Project. Lymphoblastoid cell lines from the CHB were reprogrammed to iPSCs and differentiated to cardiomyocytes using the same protocols as used for the Tibetans. The batches of 4 lines were balanced by sex and population. These iPSC-derived cardiomyocytes were cultured in hypoxia (1% O2) for 48 hours and subjected to scRNAseq in pooled batches of 3 or 4 lines. The CHB individuals included in this analysis were: NA18528, NA18531, NA18557, NA18596, NA18606, NA18608, NA18614, NA18619, NA18633, and NA18748.

  Study phs003758

• Research in Adaptive Interests, Skills, and Environment

  The Research on Adaptive Interest, Skills, and Environments (RAISE) project is a coordinated set of pilot studies funded and otherwise supported by the Center for the Study of Adolescent Risk and Resilience (C-StARR) at Duke University. The initial data collection effort (Adolescent T1; 2015; NAHDAP 100737) was conducted by telephone and focused on self-regulation and related skills during early adolescence and their role in early instances of health risk behavior. The survey was comprised of brief measures of constructs in six areas of interest to C-StARR investigators: (1) background and home environment; (2) self-regulation and personality; (3) physical and mental health; (4) problem behaviors; (5) academics and school; and (6) technology use. The representative sample of 2104 adolescents was drawn from the population of fifth through eighth graders enrolled in North Carolina public schools during the 2014-2015 school year.In 2016, a subsample of 395 participants from the Adolescent T1 survey (selected on the basis of having resided within 100 miles of study personnel hubs in Durham, North Carolina and Sylva, North Carolina) participated in an additional home visit study that involved the collection of biological data and measures of cognitive ability and executive functioning. The molecular data made available to dbGaP were obtained from saliva samples that were collected (a) in person from 377 of 395 home visit study participants and (b) by mail from 60 participants who had participated in the Adolescent T1 survey but had not participated in the home visit study. The resulting data file was imputed to a 1000G phase 3 panel and is comprised of N = 437 individuals and 7,193,135 markers after filtering. Data were filtered with MAF ≥ 0.01, HWE p-value > 10-6, and genotype rate > 95%.

  Study phs003982

• Development and validation of multivariate predictors of primary endocrine resistance to tamoxifen and aromatase inhibitors in luminal breast cancer reveal drug-specific differences

  Background: Endocrine therapy is highly effective in blocking the estrogen receptor pathway in HR+/HER2- early breast cancer (EBC). However, up to 40% of patients experience relapse during or after adjuvant endocrine therapy. Here, we investigate molecular mechanisms associated with primary resistance to endocrine therapy and develop predictive models. Results: TP53 mutations were prominently associated with primary resistance to both tamoxifen (TAM) and aromatase inhibitors (AI), with AI non-responders exhibiting resistance in up to 32% of cases. Additionally, we identified distinct DNA methylation patterns in TAM and AI non-responders, with TAM non-responders showing global DNA methylation loss, associated with KRAS signaling, apical junctions and epithelial-mesenchymal transition (EMT). Conversely, we observed methylation gain in AI non-responders affecting developmental transcription factors, hypoxia and estrogen signaling. TAM or AI resistance was associated with increased methylation-inferred proportions of immune cells and decreased proportions of endothelial cells. Based on these findings and patient age, we developed the Predictive Endocrine ResistanCe Index (PERCI). PERCI stratified NR and R cases in both treatment groups and cohorts with high accuracy (ROC AUC TAM discovery 93.9%, validation 83%; AI discovery 98.6%, validation 76.9%). A simplified PERCI efficiently predicted progression-free survival in the TCGA-BRCA sub-cohort (Kaplan-Meier log-rank p-value = 0.03 between low and high PERCI groups). Conclusions: We identified genomic and epigenomic features associated with primary resistance to TMA and AI. By combining information on genomic alterations, patient age, differential methylation and tumor microenvironment (TME) composition, we developed PERCI TAM and PERCI AI as novel predictors of primary resistance, with potential additional prognostic value. Applying PERCI in a clinical setting may allow patient-specific drug selection to overcome resistance.

  Study EGAS50000001102

• Accurate mutation detection in leukemia by re-sequencing a cancer gene set

  With the advent of whole-genome and whole-exome sequencing, high-quality catalogs of recurrently mutated cancer genes are becoming available for many cancer types. Increasing access to sequencing technology, including bench-top sequencers, provide the opportunity to re-sequence a limited set of cancer genes across a patient cohort with limited processing time. Here, we re-sequenced a set of cancer genes in T-cell acute lymphoblastic leukemia (T-ALL) using the Roche/454 technology coupled with Nimblegen sequence capture. First, we investigated how a maximal sensitivity and specificity of mutation detection can be achieved through a benchmark study. We tested nine combinations of different mapping and variant-calling methods, varied the variant calling parameters, and compared the predicted mutations with a large independent validation set obtained by capillary re-sequencing. We found that the combination of two mapping algorithms, namely BWA-SW and SSAHA2, coupled with the variant calling algorithm Atlas-SNP2 yields the highest sensitivity (95%) and the highest specificity (93%). Next, we applied this analysis pipeline to identify mutations in a set of 58 cancer genes, in a panel of 18 T-ALL cell lines and 15 T-ALL patient samples. We confirmed mutations in known T-ALL drivers, including PHF6, NF1, FBXW7, NOTCH1, KRAS, NRAS, PIK3CA, and PTEN. Interestingly, we also found mutations in several cancer genes that had not been linked to T-ALL before, including JAK3. Finally, we re-sequenced a small set of 39 candidate genes and identified recurrent mutations in TET1, SPRY3 and SPRY4. In conclusion, we established an optimized analysis pipeline for Roche/454 data that can be applied to accurately detect gene mutations in cancer, which led to the identification of several new candidate T-ALL driver mutations.

  Study EGAS00001000268

• The light chain IgLV3-21 defines a new poor prognostic subgroup in Chronic Lymphocytic Leukemia: results from a multicenter study

  Purpose: Unmutated (UM) immunoglobulin heavy chain region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21 which is potentially able to trigger cell-autonomous BCR-mediated signaling. However this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: we performed total RNA sequencing to characterize IgLV3-21 patients (n=32) and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients where IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients present higher expression of genes responsible for ribosome biogenesis and translation initiation (P<0.0001) and MYC target genes (P=0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P<0.05), in particular in IgHV mutated patients. In each of the 3 independent validation cohorts (n=813), we showed that IgLV3-21 rearrangements -similar to UM IgHV status- conferred poor prognosis compared to mutated IgHV (P<0.0001). Importantly, we confirmed in multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P<0.0001). Conclusions: We therefore demonstrate for the first time that a light chain can impact on CLL prognosis and that IgLV3-21 light chain usage defines a new poor prognostic subgroup in CLL.

  Study EGAS00001002894

• Dynamics of genomic clones in breast cancer patient xenografts at single cell resolution

  Human cancers, including breast cancers, are comprised of clones differing in mutation content that evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours has not been systematically examined at single cell resolution. Here we show by both deep genome and single cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (<5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies utilizing patient-derived breast cancer xenoengraftment.

  Study EGAS00001000952

• Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing

  Background Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer. Results We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant ‘normal’ cells or aberrant cells of unknown origin that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent, and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis. Conclusions Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

  Study EGAS00001002102

• Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

  Study EGAS00001003427