10161 results for "cancer rna-seq"

in 49.96 milliseconds.

• Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q

  Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.

  Study EGAS50000000743

• Poly(A) RNA sequencing of hepatocellular carcinoma tumors and their matched noncancerous liver tissues

  Background & Aims: The differentiation of distinct multifocal hepatocellular carcinoma (HCC): multicentric disease vs. intrahepatic metastases, in which the management and prognosis varies substantively, remains problematic. We aim to stratify multifocal HCC and identify novel diagnostic and prognostic biomarkers by performing whole genome and transcriptome sequencing, as part of a multi-omics strategy Methods: A complete collection of tumour and somatic specimens (intrahepatic HCC lesions, matched non-cancerous liver tissue and blood) were obtained from representative patientswith multifocal HCC exhibiting two distinct postsurgical courses. Whole-genome and transcriptome sequencing with genotyping were performed for each tissue specimen to con-trast genomic alterations, including hepatitis B virus integrations, somatic mutations, copy number variations, and structural variations. We then constructed a phylogenetic tree to visualise individual tumour evolution and performed functional enrichment analyses on select differentially expressed genes to elucidate biological processes involved in multifocal HCC development. Multi-omics data were integrated with detailed clinicopathological information to identify HCC biomarkers, which were further validated using a large cohort of HCC patients (n = 174).Results: The multi-omics profiling and tumour biomarkers could successfully distinguish the two multifocal HCC types, while accurately predicting clonality and aggressiveness. The dual specificity protein kinase TTK, which is a key mitotic checkpoint regulator with links to p53 signaling, was further shown to be a promising overall prognostic marker for HCC in the large patient cohort.Conclusions: Comprehensive multi-omics characterisation of multifocal tumour evolution may improve clinical decision-making, facilitate personalised medicine, and expedite identification of novel biomarkers and therapeutic targets in HCC.

  Study EGAS00001002337

• 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

• eMERGE Network's Multi-Center Pilot of Pharmacogenetic Sequencing in Clinical Practice

  eMERGE-PGx is a multi-site test of the concept that sequence information can be coupled to electronic medical records (EMRs) for use in healthcare. The promise of personalized medicine - health care guided by each individual's biological characteristics - is being fostered by increasingly powerful and economical methods to acquire clinically relevant biomarkers from large numbers of people. One therapeutic area that seems especially ripe for an early test of the personalized medicine concept is pharmacogenomics (PGx) - the idea that individual variation in drug response includes a genomic component. Drug response variation is an accepted feature of virtually all drug treatments, and contemporary molecular biologic tools continue to identify key genes mediating drug metabolism, transport, and targets. Importantly, common variation in these genes is an increasingly well-recognized contributor, sometimes with large effects, to variation in drug responses. As a result, recommendations for genotype-guided therapy are increasing. These evidence-based recommendations, if implemented in health care practice, could reduce adverse drug events and improve time to therapeutic response. Through eMERGE-PGx, we are developing strategies for the optimal implementation of genetic sequence data into the clinical environment with the ultimate goal of improving patient care. Site and participants include: Children's Hospital of Pennsylvania (CHOP): The Center for Applied Genomics (CAG) at the Children's Hospital of Philadelphia (CHOP) is a high-throughput, highly automated genotyping and sequencing facility equipped with state-of-the-art genotyping and sequencing platforms. Children who are treated at the Children's Hospital Healthcare Network and their parents may be eligible to take part in a major initiative to collect more than 100,000 blood samples, covering a wide range of pediatric diseases. The PGx population selected for sequencing with the PGRNseq panel at CHOP is 1,650 children from CAG's biorepository with well-documented drug-related severe adverse events (SAEs) or EHR-based drug response profiles. SAEs were extracted from EPIC records and from CHOP's Adverse Event (AE) database, which documents every AE at CHOP. These AEs are classified by a medical review panel according to the causal relationship with the suspected drug into 'doubtful', 'possible', and 'probable'. Individuals with events classified as probable, severe and objective, were selected for sequencing. The drugs more frequently associated with adverse events are antibiotics, antineoplastics, immunosuppressants and psychotropic drugs. This cohort constitutes 50% of the target population. The remaining subjects were selected using EHR-based algorithms that we have developed and validated at CAG for identifying patients not responding to ADHD medication (primarily atomoxetine) and patients refractory to antiepileptic treatment from responders. Cincinnati Children's Hospital Medical Center/Boston's Children's Hospital (CCHMC/BCH): 811 CCHMC samples were obtained from children, adolescents or young adults exposed to medication or at risk for needing medication of study interest. 55% of participants were exposed to one or more opioids and their DNA source was a CCHMC study-specific biobank; while 27% of participants were at risk for needing an opioid for surgical pain management and were newly recruited. The remainder of the cohort was exposed to methylphenidate and their DNA samples were obtained from a CCHMC study-specific biobank. The focus of Boston Children's Hospital eMERGE PGx project is on individuals with epilepsy. Samples were taken from a current pharmacogenomics study already in place through which DMET analysis was run and used as confirmation for PGRN-Seq results. A total of 109 samples were sent for PGRN-Seq analysis at University of Washington. The remaining 141 epilepsy samples were from Children's Hospital of Philadelphia and underwent testing with PGRN-Seq at CHOP. Geisinger Health System: A research cohort of adult Geisinger Clinic patients was enrolled from community-based primary care clinics of the Geisinger Health System. Patients were eligible for enrollment if they were a primary care patient of a Geisinger Clinic physician and were scheduled for a non-emergent clinic visit. All data are from Geisinger patients who consent to participate in the MyCode project. MyCode participants agree to provide biological samples for broad research use, including genomic analysis, and for linking of sample data to information in the participant's Geisinger health record. The consent also permits sharing of de-identified data for research purposes. Group Health(GH)/University of Washington (UW): Potential GH participants for the PGx project were enrolled in the eMERGE Network through the Northwest Institute of Genetic Medicine (NWIGM) biorepository, and provided the appropriate consent to receive clinically relevant genetic results (N~6300). Participants were eligible if aged 50 - 65 years old at the time of their enrollment into the NWIGM repository, living, enrolled in GH's integrated group practice, and had completed an online Health Risk Appraisal. The selection algorithm was based on several data sources from the EHR at Group Health: 1. Demographics - participants with self-reported race as Asian or African ancestry were prioritized and selected to enrich for non-European ancestry; 2. Diagnosis and procedure codes - participants were selected if found to have a history of hypertension, atrial fibrillation (AF,) or congestive heart failure (CHF). Participants with a history of arrhythmia were added if the entire selection algorithm did not generate 900 individuals. We also enriched for participants with EHR evidence of actionable indications related to PGRNSeq genes. Participants were selected if found to have an ICD9 code for malignant hyperthermia, hypertension, atrial fibrillation, congestive heart failure or long QT syndrome (LQTS); 3. Laboratory values - if a participant had any laboratory event of creatine kinase (CK) > 1000, and were dispensed statins within 6 months of the event, then they were selected; and 4. Medications - participants were excluded if ever on carbamazepine or had a current regimen of warfarin. Essentia Institute of Rural Health, Marshfield Clinic, Pennsylvania State University (Marshfield): For this study, 750 subjects were selected and enrolled into PGx based on Vanderbilt's algorithm designed to enrich for patients who are most likely to receive one of three common drugs (Clopidogrel, Warfarin or Simvastatin) in the next 2-3 years. These patients were sent a letter of invitation and description of the PGx project. Follow-up phone calls were made, and interested subjects came in for a one time meeting to discuss the project and go through the informed consent with the research coordinator. If they were interested they signed the consent and HIPAA forms and gave blood. Subjects were chosen and enrolled into PGx independently of previous biobank participation. Mayo Clinic: The Right Drug, Right Dose, Right Time - Using Genomic Data to Individualize Treatment (The RIGHT Protocol) enrolled 1013 patients to test the hypothesis that prescribers could deliver genome-guided drug therapy at the point-of-care by using pharmacogenomic data preemptively integrated in the electronic medical record. Complete details regarding the study population have been previously described (Bielinski et al., 2014). Icahn School of Medicine at Mount Sinai School (Mt Sinai): Our study site is the Primary Care Associates (PCA) practice group of the Mount Sinai Faculty Practice Associates (FPA) of the Mount Sinai Medical Center in New York City. This practice has 12 physician providers. All patient encounters are documented and managed with EpicCare ambulatory electronic medical record. Active PCA Patients eligible for enrollment fulfilled the following criteria: a) age 50 or older receiving clinical care at Mount Sinai FPA PCA practice with at least one practice encounter within 18 months prior to commencement of enrollment; b) no history or current use of clopidogrel, warfarin, or simvastatin. Eligible patients were invited to participate through de novo recruitment by letter sent by their provider. Interested patients were screened for eligibility and enrolled to participate in the eMERGE PGX study on site by a dedicated research coordinator. In addition to de novo enrollment from clinical practice, patients of FPA PCA who had previously enrolled in Mount Sinai's BioMe Biobank program AND fulfilled eligibility criteria as stated under a) and b) were identified by chart review and samples sequenced at CIDR using PGRNseq platform (N=300). PGRNseq data from 291 samples passed stringent quality control and are included in the current data set. Furthermore, 56 of these patients carrying known and validated 'actionable' variants affecting prescribing of clopidogrel, warfarin, and/or simvastatin were enrolled in the eMERGE PGX study following invitation through recontacting by the Principal Investigator of the BioMe Program. Northwestern University: Participants for this study were recruited from the General Internal Medicine (GIM) clinic at Northwestern Medical Group (NMG). Patients were selected for invitation to participate if they had been seen a minimum of two times over the last four years, having a high likelihood to receive a prescription for warfarin, Plavix, or a statin, and are seeing a physician who has agreed to allow their patients to be contacted for the study. We utilized an algorithm developed at Vanderbilt and tailored to our population which uses our EHR to estimate the probability that individuals will receive a prescription for warfarin, Plavix, or a statin in the next three years. Participants were sent a letter explaining the study prior to their GIM appointment and offered participation at the time of their visit. Participants were consented on-site and blood drawn after consent was obtained. The GIM clinic consists of 39 primary care physicians who provide approximately 80,000 patient encounters per year. As with any large primary care clinic, a significant proportion of patients in GIM clinic suffer from a variety of chronic health conditions, such as diabetes, hypertension, and coronary artery disease. Over 50,000 individuals have been seen by GIM doctors in the past 5 years; 11,562 of these patients have evidence of a statin prescription in the EHR, 3,436 have evidence of a warfarin prescription, and 1,872 have evidence of a Plavix prescription. Vanderbilt University: The more than 1000 participants enrolled into Vanderbilt's eMERGE PGx study were newly recruited from the Cardiology and Internal Medicine Clinics and the Hillsboro Medical Group within Vanderbilt University Medical Center (VUMC). Patients were selected based on a predictive algorithm estimating the patient's likelihood of receiving Clopidogrel, Warfarin, and/or Simvastatin. The algorithm identifies primarily older middle-aged patients, and the mean age of the study group is 74. The cohort is approximately 45% female with 75% of subjects self-identified as EA and 24% as AA. Subjects were consented in person by study personnel following a routine clinic visit and an introduction to the study staff by their doctor. VUMC is a comprehensive health care facility dedicated to patient care, research, and the education of health care professionals. Translational research into the causes and treatment of disease as well as studying fundamental biological properties is the primary focus of discovery at Vanderbilt. Clinical research is conducted in Vanderbilt University Hospital, the Nashville Veterans Administration Hospital, Meharry General Hospital and in their associated outpatient clinics. These hospitals and clinics, all associated with the Vanderbilt system, each have full time Vanderbilt faculty and medical housestaff and provide clinical care and participate in research programs. The Vanderbilt Clinic is comprised of more than 95 adult outpatient specialty practices and received over 1.5 million ambulatory visits in 2012-13. The Vanderbilt Heart and Vascular Institute offers a comprehensive heart program offering diagnosis, medical treatment, minimally invasive therapies, surgical intervention and disease management, tailored to each individual's unique needs. All programs within the Vanderbilt Clinic have survival figures that surpass the national average.

  Study phs000906

• Defective Homologous Recombination DNA Repair as Therapeutic Target in Advanced-Stage Chordoma (HIPO_021)

  HIPO project: HIPO_021 Importance: Chordomas are rare tumors of the axial skeleton and skull base with few therapeutic options and no clinically validated molecular drug targets. The value of comprehensive genomic analyses for guiding medical therapy of patients with advanced-stage chordoma is unknown.Objective: To identify therapeutically tractable genetic lesions in a cohort of chordoma patients within a genomics-guided precision oncology program and to document the outcome of individualized, molecularly targeted chordoma therapy.Design, Setting, and Participants: We performed whole-exome sequencing of tumor and matched germline control samples from seven patients with locally advanced or metastatic chordoma who were enrolled in a cross-institutional molecular stratification registry trial for younger adults with advanced-stage cancer across all histologies and patients with rare tumors. All patients were heavily pretreated and had progressive disease prior to molecular analysis.Interventions: Individualized medical therapy was administered according to the patients’ molecular profiles.Main Outcomes and Measures: Candidate therapeutic targets identified by whole-exome sequencing and response to genotype-directed therapy.Results: All patients harbored alterations of two or more genes known to be involved in DNA repair via homologous recombination (HR), including heterozygous deletions of ERCC6, FANC family members, RAD51L (n = 6), BRCA2 (n = 5), ATR, CHEK2, RAD18, RAD51B, and XRCC3 (n = 4); inactivating PTEN mutations coupled with loss of heterozygosity (n = 2); and pathogenic germline variants in BRCA2 (n = 1), NBN (n = 1), and CHEK2 (n = 1) that were accompanied by somatic deletion of the corresponding wild-type alleles. Consistently, a mutational signature associated with defective HR was enriched in all samples and co-occurred with extensive genomic instability, as evidenced by HR deficiency scores and high numbers of large-scale state transitions. These results prompted off-label treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib in a patient whose tumor was refractory to irradiation and systemic treatment with imatinib, which led to a prolonged response and substantial clinical improvement.Conclusions and Relevance: Advanced-stage chordomas are frequently characterized by genomic imprints of defective HR DNA repair. HR deficiency represents a new therapeutic opportunity in this intractable disease through repositioning of PARP inhibitors that warrants further exploration in clinical trials.

  Study EGAS00001002720

• Discrepancies in Tumour Mutation Burden (TMB) reporting from sequential Endobronchial ultrasound trans bronchial needle aspiration (EBUS TBNA) samples within single lymph node stations

  Introduction: Tumour Mutation Burden (TMB) is a potential biomarker for immune therapies. Identifying factors that may affect TMB prediction is key to its utility as biomarker for treatment options. Here we investigated parameters that might affect TMB using cytology smears obtained from endobronchial ultrasound transbronchial needle aspiration (EBUS TBNA)-sampled malignant lymph nodes, which are often the only diagnostic samples collected in patients with advanced lung cancer. Methods: Individual Diff-Quik cytology smears were prepared for each needle pass from the same enlarged malignant mediastinal lymph nodes. DNA extracted from smears of each pass underwent sequencing using a large gene panel sequencing (TSO500, Illumina). TMB was estimated for each individual needle pass using the TSO500 Local App v. 2.0 (Illumina). Results: Twenty patients had two or more Diff-Quik smears (total 45 smears) which passed sequencing quality control. Average TMB for all smears was 8.7 ± 5.0 mutations per megabase (Mb). Sixteen of the 20 patients had paired samples with minimal differences in TMB score (average difference 1.3 ± 0.85). Paired samples from 13 patients had concordant TMB in terms of scores being below or above a threshold of 10 mutations/Mb. Samples from seven patients had discrepant TMB, with four cases in particular exhibiting an average difference of 11.3 ± 2.7 mutations/Mb. Factors affecting TMB calling involved tumour content of the samples, the amount of DNA used in sequencing as well as bone fide intra tumour heterogeneity between paired samples. Conclusions: TMB assessment is feasible from EBUS-TBNA derived Diff-Quik slides from a single needle pass. Repeated samples of one or more lymph nodes have minimal variation in TMB in most cases (80%), suggesting accuracy of the test overall. To enhance accuracy of the result, care should be taken in relation to the tumour content of the cytology smear. Further, clinicians should be aware that even slight differences in lymph node site selection could give rise to variable genomics and discrepant TMB due to tumour heterogeneity. Therefore, it would be reasonable for multi-lymph node site analysis of TMB to be performed using EBUS TBNA aspirates from different easily accessible lymph nodes. Further investigations need to determine whether these samples should be combined as one sample or tested separately.

  Study EGAS00001007484

• The genomic complexity of early T-cell progenitor acute lymphoblastic leukemia

  CREST The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. T-ALL Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF), inactivating lesions disrupting haematopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1 and EP300) and histone-modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of recurrent mutation including DNM2, ECT2L and RELN. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

  Study phs000340

• Clinical outcomes in ctDNA-positive urothelial carcinoma patients treated with adjuvant immunotherapy

  Minimally invasive approaches to detect residual disease after surgery are urgently needed to select patients at highest risk for metastatic relapse for additional therapies. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease (MRD) and relapse,1-3 but its clinical value has yet to be demonstrated in a randomised clinical trial. We evaluated outcomes in post-surgical ctDNA-positive (+) patients in a randomised phase III trial of adjuvant atezolizumab versus observation. IMvigor010 enrolled 809 patients with muscle-invasive urothelial carcinoma and did not meet its primary endpoint of disease-free survival (DFS) in the intent-to-treat population. Within the study, an exploratory planned analysis of prospectively collected plasma was performed, which tested the utility of ctDNA to identify patients who may benefit from adjuvant atezolizumab treatment. ctDNA was measured at the start of therapy (cycle 1 day 1; C1D1) and at week 6 (cycle 3 day 1; C3D1), and 581 patients were evaluable for ctDNA. The prevalence of ctDNA positivity at C1D1 was 37% (n=214), and ctDNA positivity identified patients with poor prognosis (observation arm DFS HR= 6.19 (4.29, 8.91), p<0.0001). Here we show that ctDNA(+) patients had improved DFS and overall survival (OS) with atezolizumab versus observation (DFS HR= 0.56 (0.41-0.77); p=0.0003 and OS HR= 0.58 (0.4-0.86); p=0.0063). No difference in DFS or OS between arms was noted for ctDNA-negative patients. The rate of ctDNA clearance was higher with atezolizumab (18%) versus observation (4%) (p=0.0041). Transcriptomic analysis revealed that tumours from ctDNA(+) patients had higher expression of cell cycle and keratin genes. Within the ctDNA(+) patient population in the atezolizumab arm, non-relapsing patients were further enriched in prominent immune response signatures including PD-L1, IFNG, CXCL9, and high tumour mutational burden, whereas relapse was associated with angiogenesis and fibroblast-transforming growth factor-beta signatures (F-TBRS). TCGA molecular subset analysis revealed increased efficacy of atezolizumab in patients with basal-squamous tumours, consistent with underlying tumour-immune contexture. Together these findings suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in this high-risk ctDNA(+) population. These findings, if validated in other settings, would shift approaches to post-operative cancer care.

  Study EGAS00001004997

• Single cell RNA sequencing of synovial B cells in early Rheumatoid Arthritis

  This dataset includes 3432 paired single cell sequencing fastq files derived from synovial B cells of 5 early Rheumatoid Arthritis patients. Libraries were prepared using the SmartSeq2 protocol. All wells contained ERCC spike-ins. Libraries were sequenced on an Illumina NovaSeq instrument with 2x100bp paired-end reads yielding a median of 2.5M reads/well. Sample aliases ending on 368 and 384 represent empty control wells. Sample aliases starting with P11417_4 and P13157_1 belong to ACPA- patient A7, sample aliases starting with P11417_5 and P11417_6 belong to ACPA+ patient A1, sample aliases starting with P13157_2 belong to ACPA- patient A3, sample aliases starting with P13157_3 and P13157_6 belong to ACPA+ patient A2, sample aliases starting with P13157_4 and P13157_5 belong to ACPA- patient A4.

  Dataset EGAD00001009076

• Mechanisms_of_patient_response_to_Dabrafenib_in_Melanoma

  Samples will be from the BRF113683 (BREAK-3) study which is a Phase III Randomized, Open-label Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (n=250 enrolled)•NGS [Agilent capture (Sanger V2 panel): 360 genes and 20 gene fusions; Illumina HiSEQ Sequencing]•CNV: [via NGS or Affy SNP 6.0 or Illumina Omni (TBD)]Bioinformatics: Analysis will be performed using core Sanger informatics pipelines similar to those previously described (Papaemmanuil E et al. (2013) Blood. 22:3616 -3627). Briefly, copy number analysis will be performed using the ASCAT algorithm, and base substitutions, small insertions and deletions using the CAVEMAN and Pindel algorithms, respectively. Statistical approaches including generalized linear models will be used to predict clinical variables such as maximum clinical response and duration of response using genetic data. Sanger and EBI to conduct analysis; Raw data and correlation with clinical endpoints to be analyzed by both EBI/Sanger and GSK (unique pipeline analyses to increase call confidence)

  Study EGAS00001000946