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• Response and Resistance to ER-Directed Therapy in Metastatic Breast Cancer

  Despite the reduction in cancer recurrence and mortality provided by hormonal therapy, estrogen receptor positive (ER+) metastatic breast cancer (MBC) remains the most common cause of breast cancer death, resulting in more than 20,000 deaths in the U.S each year. Although several therapeutic options exist to target the estrogen receptor, resistance to these therapies invariably occurs. Genetic mechanisms of acquired resistance to targeted therapies in ER+ MBC are not well understood. To address this, we developed a prospective biopsy protocol where multiple research biopsies are collected from metastatic samples and used for pathology, ER/PR/HER2, OncoPanel (a CLIA 300 gene sequencing panel), whole exome sequencing (WES), transcriptome sequencing (RNA-Seq), and single-cell RNA-seq (scRNA-seq). In some cases, tissue is used for cell line and xenograft generation. Archival primary biopsies are also obtained when possible for parallel genomic studies. Patients are followed and serial metastatic biopsies are obtained. This data will be used to determine the landscape of genomic alterations in treatment-resistant ER+ MBC, and compared to data generated by TCGA for treatment-naive ER+ primary breast cancer. Comparison of genomic studies from resistant, metastatic specimens with corresponding pre-treatment primary samples will allow us to identify genomic association with resistance to specific therapies. Analysis of the serial metastatic biopsies collected over the course of multiple treatments will also shed light on tumor evolution under selective therapeutic pressure.NoteA subset of the MBC blood biopsies that are included in our study can be accessed and downloaded from the phs001977 accession.Another subset of patients in this study participated in a clinical trial (NCT02871791) and have their data deposited in the current study as well.

  Study phs001285

• IL7-receptor expression is frequent in T-cell acute lymphoblastic leukemia and predicts sensitivity to JAK-inhibition

  T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with a dismal prognosis related to refractory/relapsing diseases, raising the need for new targeted-therapies. Activating mutations of the IL7-receptor pathway genes (IL7Rp) play a proven leukemia-supportive role in T-ALL. JAK-inhibitors such as ruxolitinib have recently demonstrated preclinical efficacy. However, prediction markers for sensitivity to JAK-inhibitors are still lacking. Herein, we show that IL7R (CD127) expression is more frequent (~70%) than IL7Rp-mutations in T-ALL (~30%). We compared the so-called non-expressers (no IL7R-expression/IL7Rp-mutation), expressers (IL7R-expression without IL7Rp-mutation) and mutants (IL7Rp-mutations). Integrative multi-omics analysis outlined IL7R-deregulation in virtually all T-ALL subtypes, at the epigenetic-level in non-expressers, genetic-level in mutants, and post-transcriptional level in expressers. Ex-vivo data using primary-derived xenografts support that IL7Rp is functional whenever the IL7R is expressed, regardless of the IL7Rp mutational status. Consequently, ruxolitinib impaired T-ALL survival in both expressers and mutants. Interestingly, we show that expressers displayed ectopic IL7R-expression and IL7Rp-addiction conferring a deeper sensitivity to ruxolitinib. Conversely, mutants were more sensitive to venetoclax than expressers. Overall, combination of ruxolitinib and venetoclax resulted in synergistic effects in both groups. We illustrate the clinical relevance of this association by reporting achievement of complete remission in two patients with refractory/relapsed-T-ALL. This provides proof of concept for translation of this strategy into clinics as bridge to transplant. Altogether, IL7R-expression can be used as a biomarker for sensitivity to JAK-inhibition, thereby expanding the fraction of T-ALL patients eligible to ruxolitinib up to nearly ~70% of T-ALL.

  Study EGAS00001007144

• Genome-Wide Analysis for Addiction Susceptibility Genes

  Genome wide analysis for addiction susceptibility genes is an affected sibling pair linkage study using subjects who were patients in methadone replacement treatment programs (MMTP). Such patients are highly addicted to opioids and usually to other addicting substances as well. For entry into the programs, patients had to be at least 18 years of age and had to satisfy DSM-IV criteria for opioid dependence. Despite their common substance use disorder diagnosis, patients enrolled in MMTPs generally have a heterogeneous mix of co-morbid psychiatric disorders including anti-social personality disorder, major depression and anxiety disorders, and often satisfy DSM-IV criteria of substance use disorders other than opioid dependence. Genetic analysis was carried out using genotyping data obtained from a 10K SNP array, and non-parametric linkage was assessed using MERLIN. This resulted in the identification of a linkage peak on 14q that overlapped the NRXN3 gene (neurexin 3), which was previously identified as a potential candidate gene for addiction, and subsequently identified as a target gene in other addiction studies and autism. In version 2 of this study, a text file containing 7704 SNPs with large allele frequency discrepancy as compared to 1000 Genomes is included. Users have the option to exlude these 7704 SNPs.

  Study phs001266

• Enrichment of PTPRT and JAK2 mutations in lung cancer from African Americans and evidence for increased GI and HRD in LUSC

  The goal of this study is to compare the somatic mutation landscape between European Americans and African Americans. It includes various histological forms of lung cancer. In LUAD, we find increased prevalence of PTPRT and JAK2 mutations among African Americans. These proteins function in the same pathway and as such, this may be a new actionable target for lung cancer. We have also examined the landscape of copy number profiles in African Americans and European Americans.

  Study phs001895

• ATAC-seq iPSC cells or smNPC cells for allelic imbalance

  In order to confirm the predicted impact of the PD-associated allele of rs144814361 on BAG3 promoter, we proceeded with genome editing of the TH-REP1 cell line by using prime editing to insert the “T” allele at the position chr10:119651405 in the BAG3 promoter. 3 replicates for each condition: 1) iPSC Wild Type 2) SNP-BAG3 variant in iPSC 3) SNP-BAG3 variant in smNPC. Allelic imbalance is further assessed using read counting at this specific position.

  Study EGAS50000001579

• Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

  FOXO1 has an oncogenic role in adult germinal center derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1 resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3 or members of the phosphatidylinositol 3’ OH kinase (PI3K) signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

  Study EGAS00001003719

• A Phase 2 Study of Lamivudine in Patients with p53 Mutant Metastatic Colorectal Cancer

  This was an open-label, single-arm Phase II study of lamivudine in patients who had progressed on systemic therapy for advanced colorectal cancer with TP53 mutations. The phase II study had a two-stage design, with a target accrual of 20 evaluable patients for the first stage and a total of 32 patients for the whole study. The first 9 patients were treated with lamivudine at 150 mg PO bid continuously for 28-day cycles. Subsequent patients (10-32) received a higher dose of 600 mg PO bid continuously for 28-day cycles. Tumor assessments were performed every 8 weeks until documented disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) or drug intolerance. Whole genome sequencing (WGS) and total RNA-seq were performed on pre- and post- treatment biopsies on this trial.

  Study phs002833

• From matrimonial practices to genetic diversity in Southeast Asian populations: the signature of the matrilineal puzzle

  This project aims at revisiting the "matrilineal puzzle" from a population genetics' point of view. The dataset consists of 719 individuals from 12 populations sampled in continental Southeast Asia and genotyped at 598764 loci. This dataset can only be accessed and used for non-commercial research purposes with a finality complying with the informed consent provided by donors. For accessing the data, please provide: 1. An explicit title for the project you wish to use the data for. 2. A detailed institutional affiliation of all recipients and users of the data. 3. A summary (500 words) of the research project, with emphasis on its scientific and societal finality, and predicted outputs. If access is granted by the DAC, data cannot be shared with a third party not initially involved in the project, without the third party officially applying for accessing the data.

  Study EGAS00001003727

• The Surveillance Monitoring for ART Toxicities (SMARTT) and the Women and Infants Transmission Study (WITS)

  Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor (NRTI) which competitively inhibits HIV reverse transcriptase and is incorporated into the viral DNA, resulting in DNA chain termination. It was the first approved antiretroviral medication used for preventing HIV transmission from mother to child. However, in vitro and animal studies have suggested genotoxicity of ZDV and no study has evaluated potential impact of in utero ZDV exposure using genomic sequencing technologies. In this study, we investigate markers of genomic damage detected in peripheral blood mononuclear cell samples obtained from 91 ZDV-exposed and, for comparison, 94 NRTI-unexposed HIV-uninfected children born to HIV-infected mothers during the first week after birth. We utilize high-throughput DNA sequencing (whole exome sequencing) and genotype array methods to comprehensively identify potential clonal somatic single nucleotide variants (SNVs) and large acquired copy number alterations (SCNAs) related to ZDV exposure.

  Study phs002061

• Gene Variants in Pheochromocytoma and Paraganglioma

  Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arise from chromaffin cells in the adrenal medulla and in extra-adrenal locations, respectively. PPGL has the strongest hereditary risk of all endocrine neoplasms with about 40% of cases harboring germline mutations and another 25-30% of cases arising from somatic mutations. To date, over 20 susceptibility genes have been suggested to play a role in PPGL pathogenesis, with more genes still being researched. This project will seek to identify new candidate genes in apparently sporadic PPGLs to reveal a possible genetic background in cases without variants in known susceptibility genes. Knowledge of the genetic background and the genes involved in the pathogenesis of PPGL allows for clustering and/or development of targeted therapies for the tumors that cannot be surgically resected or tumors that have metastasized.

  Study phs002405