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• OpACIN-neo – A Multicenter Phase 2 Study to identify the Optimal neo-Adjuvant Combination scheme of Ipilimumab and Nivolumab – RNA sequencing

  The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo study (NCT02977052) to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. 86 patients with macroscopic stage III melanoma were randomised to one of three dosing schedules: arm A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks; arm B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks; or arm C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3mg/kg once every 2 weeks. Within the first 12 weeks, grade 3–4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. Pathological responses occurred in 24 (80%) patients in group A, 23 (77%) in group B, and 17 (65%) in group C. The 2-year estimated relapse-free survival was 84% for all patients, 97% for patients achieving a pathologic response and 36% for nonresponders (p<0.001). High tumor mutational burden (TMB) and high interferon-gamma-related gene expression signature score (IFN-γ score) were associated with pathologic response and low risk of relapse; pathologic response rate (pRR) was 100% in patients with high IFN-γ score/high TMB, patients with high IFN-γ score/low TMB or low IFN-γ score/high TMB had pRRs of 91% and 88%; while patients with low IFN-γ score/low TMB had a pRR of only 39%. These data demonstrate long-term benefit in patients with a pathologic response and show the predictive potential of TMB and IFN-γ score.

  Study EGAS00001004833

• NHLBI TOPMed: Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

  During Visit One, the PUSH Study will perform echocardiography on 600 children and adolescent with patients with sickle cell disease (SCD) and 100 control children and adolescents at three Field Centers, namely Howard University, Children's National Medical Center and University of Michigan. Patients or their parents will be approached and asked to give informed consent. If they appear to have a difficult reading, reading of the consent will be offered. Patients or their parents not appearing to comprehend the consent will not be eligible. As a part of this visit, each participant or parent will sign informed consent, complete a Participant Contact Information Form, complete a Medical History Form, undergo physical examination with completion of a Physical Examination Form and have blood drawn. Each participant must have echocardiography performed with measurement of Tricuspid Regurgitant Jet Velocity (TRV). In addition, attempts will be made 1) to perform a six-minute walk test, 2) to collect information from a recent (within six months) Transcranial Doppler Study (TCD) or to perform TCD, and 3) to perform pulmonary function tests. Study personnel will review all forms for completeness and conduct phlebotomy. Blood will be shipped to the Central Lab. Results of all procedures and tests will be transmitted to the Data Manager at Howard University. Sequencing was only done on sickle cell participants.

  Study phs001682

• Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients.

  Whole Exome and Target Sequencing Data in 75 Samples from 5 Hepatocellular Carcinoma Patients. The sequencing was performed by Illumina HiSeq 4000. Background and aims: Intratumoral heterogeneity (ITH) challenges identifying mutations with target therapy potential whereas circulating cell-free DNAs (cfDNAs) could reflect nearly the entire mutation spectrum in given tumors. We investigated how to minimize the limit of ITH for profiling hepatocellular carcinoma (HCC).Methods: Thirty-two multi-regional HCC samples from five patients were subjected to whole exome sequencing (WES) and targeted deep sequencing (TDS). ITH extent was measured by the average percentage of non-ubiquitous mutations (present in parts of tumor regions). Matched cfDNAs were also analyzed by WES and TDS. Profiling efficiencies of single tumor specimen and cfDNA were compared and the one better depicted mutational landscape was selected to screen therapeutic targets.Results: We found variable extents of ITH in HCCs and observed branched and parallel evolution patterns. ITH level decreased at higher sequencing depth of TDS than that measured by WES (28.1% vs 34.9%, P < 0.01) but it remained unchanged upon additional samples analyzed. TDS of single tumor specimen detected an average of 70% the total mutations in HCC. Although more mutations were detected in cfDNA under TDS than WES, an average of 47.2% total HCC mutations uncovered by cfDNA suggested tissue outperform cfDNA and the latter may serve as alternative in profiling HCC genome. Consequently, TDS of single tumor tissue in 66 patients and cfDNAs in four unresectable HCCs identified 38.6% (26/66 and 1/4) patients bearing therapeutic targets.Conclusions: TDS of single tumor specimen could largely circumvent ITH to uncover mutations indicative of target therapy in HCC.

  Dataset EGAD00001003278

• Postmortem Analysis of the Caudate Nucleus in Schizophrenia

  This postmortem study examines genomic signatures (gene, transcript, exon, and exon-exon junction) in the caudate nucleus of individuals with or without psychiatric illnesses. We characterized genetic and epigenetic changes across the lifespan of 443 donor subjects, including 245 individuals without psychiatric illness, 154 individuals with schizophrenia, and 44 individuals with bipolar disorder. The subjects are 210 from African and 233 from European ancestries. Combining expression quantitative trait loci (eQTL) analysis, Mendelian randomization with the latest schizophrenia genome-wide association study (GWAS), transcriptome-wide association study (TWAS) and differential expression analysis, we identified many genes associated with schizophrenia risk, including potentially the dopamine D2 receptor short isoform. We found that antipsychotic medication has an extensive influence on caudate gene expression. We constructed caudate nucleus gene expression networks that highlight interactions involving schizophrenia risk. These analyses provide a resource for the study of schizophrenia and insights into risk mechanisms and potential therapeutic targets. There are 120 subjects in this study which are also present in the study phs000417.

  Study phs003495

• Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofibromatosis type 1-associated atypical neurofibromas

  Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from pre-existing benign plexiform neurofibromas (PN) and atypical neurofibromas (ANF). ANF are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. In the first comprehensive genomic analysis of ANF, we performed tumor/normal exome sequencing (ES) of 16 ANFs. In addition, we conducted ES of three MPNSTs, copy-number meta-analysis of 26 ANF and 28 MPNST, and whole transcriptome RNA-seq analysis of five ANF and five MPNST. We identified low mutation burden (median 1, range 0-5) in the exomes of ANF (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/CDKN2B (69%) and SMARCA2(42%) loci. We determined that polycomb repressor complex 2 (PRC2) genes EED or SUZ12 were frequently mutated, deleted or downregulated in MPNST but not in ANF. Our gene expression study revealed upregulated NRAS, MDM2, CCND1/CCND2/CCND3 and CDK4/CDK6 in both ANF and MPNST, and overexpression of EZH2 in MPNST only. We conclude that the PN-ANF transition is primarily driven by the deletion of CDKN2A/CDKN2B in addition to already present inactivated NF1. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction, cell cycle and pluripotency self-renewal genes.

  Study phs001993

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274

• Exome Sequencing of a family with thrombocytopenia, red cell macrocytosis, and lymphoblastic leukemia predisposition

  A family with a history of bleeding, variable thrombocytopenia, red cell macrocytosis and two cases of pre B-cell acute lymphoblastic leukemia was studied in a single visit. The family was assessed for bleeding history using a bleeding questionnaire. Additionally, complete blood counts were measured and whole blood was collected from five affected individuals and three unaffected individuals for DNA extraction and whole exome sequencing. The goal of this study is to determine the genetic cause of thrombocytopenia, red cell macrocytosis, and predisposition to leukemia in a family. It is hoped that the information obtained from this study will help researchers understand the genetic and molecular basis of platelet and red cell production, as well as leukemia predisposition.

  Study phs000873

• International Verapamil SR/Trandolapril [INVEST] Genes Study

  INternational VErapamil SR-Trandolapril STudy (INVEST) was a prospective, multicenter, randomized, open-label, parallel-clinical trial that evaluated blood pressure response and adverse outcomes in patients randomized to either an atenolol-based or a verapamil SR-based hypertension treatment strategy in 22,576 patients with documented coronary artery disease and hypertension (PMID: 9809930,14657064). Hydrochlorothiazide and trandolapril were added as needed to achieve BP control or end organ protection in a protocol-defined manner. Briefly, the protocol required patients to be followed up at bassline, 6, 12, 18 and 24 weeks and then every 6 months thereafter until 2 years after the last patient was enrolled. At each visit, patients had BP and heart rate measured, clinical assessment performed, and additional antihypertensive medications added as needed to meet JNC VI blood pressure goals. The primary outcome was the first occurrence of all-cause death, nonfatal myocardial infarction (MI), or nonfatal stroke (clinicaltrials.gov identifier: NCT00133692). The genetic substudy of INVEST, INVEST-GENES, collected genomic DNA samples from 5,979 INVEST study participants. INVEST-GENES samples were genotyped on the Illumina OmniExpressExome GWAS chip. This data release includes 1529 samples that passed quality control including 657 whites, 537 Hispanics and 155 blacks. Two case-control subsets were created: one for the primary outcome of all-cause death, nonfatal MI or nonfatal stroke; the other one is for new-onset diabetes. Resistant hypertension was also evaluated in 1349 participants based on the medication use and blood pressure measurements at the visit prior to experiencing study outcomes or censoring (PMID:30237584).

  Study phs002319

• Multi-omic analysis of SDHB-related PCPG

  Hereditary SDHB-mutant pheochromocytomas (PC) and paragangliomas (PG) are rare tumours with a high propensity to metastasize although their clinical behaviour is unpredictable. To characterize the genomic landscape of these tumours and identify metastasis biomarkers, we performed multi-omic analysis on 94 tumours from 79 patients using six molecular methods including: whole-genome sequencing (WGS) of tumour and matched blood (n=94), whole transcriptome sequencing (RNA-seq) (n=91), small-RNA seq (n=90), DNA methylation profiling (n=93). Droplet-based (10x) single nuclei (sn)RNA-seq and snATAC-seq was applied to 9 and 7 cases, respectively. Additionally snATAC-seq was applied to one sample of normal adrenal medulla.

  Study EGAS50000000346