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• DAXX restoration suppresses alternative lengthening of telomeres in ATRX wild-type cells

  Many tumors maintain chromosome ends through a telomerase-independent, homologous recombination based mechanism called alternative lengthening of telomeres (ALT). While ALT occurs in only a subset of tumors, it is strongly associated with mutations in the genes encoding components of the histone H3.3 chaperone complex, ATRX and DAXX. To date the mechanistic role of ATRX and particularly DAXX mutations in potentiating ALT remains poorly understood. We identify an osteosarcoma cell line, G292, with a unique chromosomal translocation resulting in loss of DAXX function, while retaining functional ATRX. Using this distinctive resource, we demonstrate that introduction of wild type DAXX suppresses the ALT phenotype and restores localization of the ATRX/DAXX complex to PML bodies. This provides the first direct molecular evidence that ongoing DAXX deficiency is essential for maintenance of the ALT phenotype and highlights the potential for therapeutic targeting of this oncogenic pathway.

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• Massachusetts General Hospital (MGH) Atrial Fibrillation Study

  The Massachusetts General Hospital (MGH) Atrial Fibrillation Study was initiated in 2001. The study has enrolled serial probands, unaffected and affected family members with atrial fibrillation. At enrollment participants undergo a structured interview to systematically capture their past medical history, AF treatments, and family history. An electrocardiogram is performed; the results of an echocardiogram are obtained; and blood samples are obtained. The Massachusetts General Hospital (MGH) Atrial Fibrillation Study is utilized in the following dbGaP substudies. To view genotypes, analysis, other molecular data, and derived variables collected in these substudies, please click on the following substudies below or in the "Substudies" box located on the right hand side of this top-level study page phs001001 Massachusetts General Hospital (MGH) Atrial Fibrillation Study. phs001116 MGH AF CHARGE-S phs001117 MGH AF Exome Sequencing phs001118 MGH AF Medical Resequencing

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• Characterization of X Chromosome Inactivation Using Integrated Analysis of Whole-Exome and mRNA Sequencing

  This study of DNA and RNA sequencing of 5 parent-offspring trios is a single center study. The goal of this study is to characterize X chromosome inactivation (XCI) ratio in females using phased genomic variations obtained through whole genome or exome sequencing in trios, followed by allele-specific expression analysis of the phased, heterozygous alleles in the mRNA of the female offspring, and to apply this method to clinical diagnosis. The distribution of allele ratios across X obtained from mRNA sequencing allows for the estimation of X inactivation status of inherited X chromosomes, and the parameters of each parental allele distributions in the offspring's mRNA data can be used as determinants for XCI ratio. This approach was used to evaluate the contribution of skewed XCI ratio to phenotypic heterogeneity in an undiagnosed, mild neurological condition.

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• ASsessing and Predicting Infant RSV Effects and Severity (AsPIRES) Study

  A prospective multi-year clinical translational study including three cohorts of term infants experiencing their first Respiratory Syncytial Virus (RSV) season. All infants are less than or equal to nine months of age at study entry. The three subject cohorts represent the full spectrum of RSV disease severity and include a birth cohort, a cohort of infants hospitalized for RSV disease and infants evaluated at ambulatory settings for RSV infection. All infants are followed longitudinally and evaluated at recognition of acute RSV infection and twice during convalescence. Innate and adaptive immune status are comprehensively measured in association with clinical, environmental, viral, and bacteriologic factors. Genome-wide expression is assessed in the nasal airways, and in sorted peripheral blood lymphocytes. The study goal is to Identify host responses to RSV infection and factors associated with severe disease.

  Study phs001201

• Natural History of and Genetic Modifiers in Spinocerebellar Ataxias

  Spinocerebellar ataxias (SCA) are genetic neurological diseases that cause imbalance, poor coordination, and speech difficulties. There are different kinds of SCA and this study will focus on types 1, 2, 3, and 6 (SCA 1, SCA 2, SCA 3, also known as Machado-Joseph disease and SCA 6). The diseases are rare, slowly progressive, cause increasingly severe neurological difficulties and are variable across and within genotypes. The purpose of this research study is to bring together a group of experts in the field of SCA for the purpose of learning more about the disease. The research questions are: How does the disease progress over time? What are the best ways to measure disease progression? Do some genes, other than the gene that is abnormal in the SCA disease, have any effect on the way the disease behaves?

  Study phs001332

• MP2PRT: Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2

  The Molecular Profiling to Predict Response to Treatment (MP2PRT) program is part of the NCI's Cancer Moonshot Initiative. The aim of this program is the retrospective characterization and analysis of biospecimens collected from completed NCI-sponsored trials of the National Clinical Trials Network and the NCI Community Oncology Research Program. This study, titled "Identification of Genetic Changes Associated with Relapse and/or Adaptive Resistance in Patients Registered as Favorable Histology Wilms Tumor on AREN03B2", performs genomic characterization (WGS 30X, Total RNAseq, miRNAseq) on a discovery set of 70 trio cases (normal tissue, tumor tissue at time of diagnosis, tumor tissue at time of relapse) from patients who relapsed with Favorable Histology Wilms Tumor. Prioritized findings from the discovery set will be validated using Targeted Sequencing in an independent validation set of 47 relapse samples.

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• National Institutes of Health H3Africa African Collaborative Center for Microbiome and Genomics Research (ACCME)

  The African Collaborative Center for Microbiome and Genomics Research is a multi-institutional collaborative research project. The objectives of the project are to collaborate and implement high impact integrative epidemiology and genomics research into discovery of biomarkers associated with cervical carcinogenesis. Specifically ACCME links and leverages existing funded research and program activities at the collaborating institutions to study the interaction between vaginal microbiome, host genetic factors and molecular variants of Human Papilloma Virus (HPV) to determine correlates of viral persistence in the causal pathway of cervical cancer, a major cause of preventable mortality in Nigeria and other parts of sub-Saharan Africa. This research offers several opportunities to advance understanding of cervical carcinogenesis, viral oncogenesis, new biomarker discovery and risk stratification by genotype in a cohort of African women. Sponsorship: This project is sponsored by the National Institutes of Health (NIH)

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• PDAC Prognosis Biomarkers in Genomic and Transcriptomic Molecular Data

  Our study was designed to identify biomarkers related to the prognosis of Pancreatic Ductal AdenoCarcinoma (PDAC) patients using genomic variants and gene expression in coding regions of the human genome (exome). PDAC is the 7th cause of cancer deaths and is among types of cancer having the poorest prognosis. To improve treatment outcomes of PDAC, biomarkers related to PDAC prognosis are needed. The goals of our study are to find genomic and transcriptomic biomarkers, which can classify prognosis subtype of PDAC patients, and eventually to predict subtypes or prognosis for each patient. In this study, we generated Whole Exome Sequencing (WES) and exome capture RNA sequencing data of 450 tumor and matched normal samples from 150 PDAC patients. Our data may be useful for understanding genomic and transcriptomic features, prognosis prediction, and precision medicine for PDAC.

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• HCI-PDX Trial Center for Breast Cancer Therapy

  The HCI-PDX Trial Center for Breast Cancer Therapy study is a collection of patient-tumor samples that are serially established as patient-derived tumor xenografts (human tumor in mouse) and matching organoids. For this study, we describe valuable methods and resources to generate organoids and use them as cost-effective models for precision drug screens. This study leveraged whole-exome sequencing, RNAseq, and SNP-array data to illustrate how the heterogeneity of tumors is preserved in xenograft and organoid models. Sequencing files are provided for whole-exome and RNAseq data. Processed copy number variant calls from the SNP arrays are also available. A full description of the study can be found in the article entitled, "A human breast cancer-derived xenograft and organoid platform for drug discovery and precision oncology," written by Guillen et al., 2022 in Nature Cancer (PMID: 35221336).

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• Genomic analysis of primary plasma cell leukemia reveals complex structural alterations and high risk mutational patterns

  Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) that is characterized by poor overall survival despite advances in anti-MM therapy. The disease biology as well as molecular mechanisms that distinguish pPCL from non-pPCL MM remain poorly understood. In an attempt to identify key biological mechanisms that result in the aggressive pPCL phenotype we performed whole exome sequencing in 23 patients with newly diagnosed pPCL. The results reveal an enrichment of complex structural changes and high risk mutational patterns in pPCL that explain, at least in part, the aggressive nature of the disease. In particular pPCL patients with traditional low risk features such as translocation t(11;14) or hyperdiploidy accumulated adverse risk genetic events that could account for the poor outcome in this group.

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