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• Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

  The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by Homologous Recombination (HR). Here we show that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual revealed congenital abnormalities characteristic for FA. Cells from the patient, carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3, show increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival and cell cycle arrest in G2 phase. The cellular phenotype is mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or by introduction of the patient-derived missense mutation, and is rescued by expression of wildtype RFWD3 protein. HR is disrupted in RFWD3 mutant cells, caused by impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with RPA. Rfwd3 knockout mice exhibit increased embryonic lethality, are sub-fertile, show ovarian and testicular atrophy and have a reduced life span in which they resemble other FA mouse models. Although mutation was detected in a single child with FA yet, we propose RFWD3 as a novel FA gene, FANCW, supported by cellular paradigm systems and an animal model.

  Study EGAS00001002440

• Whole Exome Sequencing of Human Gastro-esophageal Cancer PDXs

  The dataset includes 51 whole exome sequencing datasets generated using Illumina paired-end sequencing technology. These data derive from 26 patient-derived xenograft (PDX) tumors and their matched normal tissues, which consist of either normal gastric mucosa or blood samples. In one case (GTR0607), the matched normal tissue data are unavailable. As a result, the dataset comprises 102 FASTQ files, providing raw sequencing reads for comprehensive genomic analysis.

  Dataset EGAD50000001407

• NHLBI TOPMed: TReating Children to Prevent EXacerbations of Asthma (TREXA)

  TREXA is a 44-week randomized, double-blind, double-masked, four-treatment, parallel trial that will evaluate the weaning strategy that provides the best protection against the development of exacerbations in children whose asthma is acceptably controlled on a low dose of ICS (per NAEPP guidelines). Following the 4 weeks of the run-in period on a 1x dose of ICS (100 µg fluticasone b.i.d. or its equivalent), children who do not meet the definition of acceptable asthma control will be randomized to the parallel BADGER protocol; those who meet the definition of acceptable asthma control will be enrolled into the 44-week treatment phase of the study. The primary outcome measure will be time to first exacerbation requiring a prednisone course.

  Study phs001732

• Refractory Classic Hodgkins Lymphoma (cHL) sWGS

  Associated with the study: Blood-based Monitoring of Relapsed/Refractory Hodgkin Lymphoma Patients Predict Responses to Anti-PD-1 Treatment. 26 ctDNA Samples from 4 patients followed longitudinally. sWGS performed for copy number aberration (CNA) analysis.

  Dataset EGAD50000001163

• Dental Caries: Whole Genome Association and Gene x Environment Studies

  Dental caries (also known as tooth decay) remains the most common chronic disease of childhood, five times more common than asthma and seven times more common than environmental allergies, with more than 40% of children exhibiting caries when they enter kindergarten. In 2005, it was estimated that dental health care costs were approximately $84 billion, of which 60% or about $50 billion were related to treatment of dental caries. Although overall caries prevalence has declined over the last 40 years, dental caries in the primary dentition and mean caries rates in children ages 2-11 has increased markedly over the past 12 years. Childhood caries is a serious public health issue because of associated health problems and because disparities in oral health have led to substantially higher average disease prevalence among children in poverty and in under-served racial and ethnic groups. These issues are of such concern that in 2005, the American Academy of Pediatrics made children's oral health one of their top areas of focus, as it is for the majority of the NIDCR "Disparities Centers". The etiology of dental caries has been studied for many years. Multiple factors contribute to a person's risk for caries, including: 1) environmental factors such as diet, oral hygiene, fluoride exposure and the level of colonization of cariogenic bacteria and 2) host factors such as salivary flow, salivary buffering capacity, position of teeth relative to each other, surface characteristics of tooth enamel and depth of occlusal fissures on posterior teeth. In spite of all that is known about this disease, there are still individuals who appear to be more susceptible to caries and those who are extremely resistant, regardless of the environmental risk factors to which they are exposed, implying that genetic factors also play an important role in caries etiology. This conclusion is supported by studies in both humans and animals, with the most compelling evidence coming from studies of twins reared apart in which investigators found significant resemblance within monozygotic (MZ) but not dizygotic (DZ) twin pairs for percentage of teeth and surfaces restored or carious and estimated the genetic contribution to caries as 40%. Other recent studies of twins reared together estimated the heritability for caries, adjusted for age and gender, as ranging from 45-64%. Despite the strong evidence of a genetic component to risk for dental caries, there have been only a few studies of candidate genes in caries, and no published genome-wide scans. A comprehensive genome wide search is the only approach that will allow us to identify those genetic regions likely to harbor genes increasing the risk for dental caries, and eventually to identify the etiologic genes and to explore the interaction of those genes with microbiological, dietary, fluoride, and behavioral factors that are known to be associated with caries risk and progression. Therefore, the goal of this study is to perform genome-wide association (GWA) studies of dental caries with a large panel of SNP's (610,000) in families and individuals ascertained through multiple US sites (University of Pittsburgh and University of Iowa). The v2 release of this study includes 96 additional individuals who were genotyped with the CCDG: Dental Caries and CL/P in Guatemala project (dbGaP accession number phs000440) to augment the data initially presented here. These subjects were genotyped on the Illumina 610 platform to make their data comparable. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org), which was developed through the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to dental caries through large-scale genome-wide association studies of well-characterized families and individuals at multiple sites in the U.S. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). The study was supported by the National Institute of Dental and Craniofacial Research (NIDCR, U01-DE018903). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington. Samples of some participants in this study were selected for further genomic analysis. These results will be available in the dbGaP CIDR study: Center for Oral Health Research in Appalachia (COHRA) Genomic Studies of Oral Health and Disease (phs001591).

  Study phs000095

• Host whole genome variations are associated with neurocognitive outcome in survivors of pediatric medulloblastoma

  Host whole genome analysis is a promising source of predictive information for long-term morbidity in cancer survivors. However, studies on genetic predictors of long-term outcome, particularly neurocognitive function following chemoradiation in pediatric oncology are limited. In the present study, we evaluated variations in host whole genome single nucleotide polymorphisms (SNPs) and their association with cognitive outcome. Whole-genome SNP analysis of host peripheral blood was conducted on 22 medulloblastoma long-term survivors, of whom 18 completed neuropsychological testing. First, unsupervised consensus clustering of the most variable SNPs within 409 genes involved in DNA repair was performed. Discrete variant groups were identified, although they were not associated with cognitive outcome, suggesting that variations in genes corresponding to a single functional group may be insufficient to predict long-term outcome alone. In support of this interpretation, unsupervised hierarchical clustering analysis using disease-associated gene variants by cognitive impairment status yielded two distinct variant clusters comprised of 36 variants, 34 of which were in noncoding regions. These findings illustrate for the first time that cognitively impaired survivors have a distinct variant profile compared to other medulloblastoma survivors. Future research in larger cohorts is needed to validate host genome predictors of cognitive impairment that may impact clinical management.

  Study EGAS00001002996

• Study of Environment, Lifestyle and Fibroids SNP Data

  Uterine fibroids are hormonally-dependent benign tumors of the uterine muscle that develop in premenopausal women. Currently, the primary symptoms (pain and bleeding) are treated, but when those treatments fail, major procedures to remove or shrink the fibroids are frequently the only options for women. Fibroids are the leading indication for hysterectomy in the United States. African-American women develop fibroids an average of 10 years earlier than white women in the U.S., and they are approximately three times more likely to have a hysterectomy for fibroids. The known risk factors for fibroids do not explain this disparity.The goal of the Study of Environment, Lifestyle & Fibroids (SELF) is to identify risk factors for uterine fibroid development. It is the first study to identify incident cases based on ultrasound screening. We enrolled a cohort of 1693 women who self-identified as Black or African American, ages 23-35, from the Detroit, Michigan area. Women with a prior diagnosis of fibroids were not eligible. Participants were screened for fibroids with ultrasound at enrollment, and follow-up ultrasounds occurred approximately every 20 months to identify new fibroids. Fibroids that were detected at enrollment and those that arose during follow up were monitored at subsequent visits for fibroid growth. We collected risk factor and symptom data, physical measurements, as well as blood, urine, and vaginal swab specimens at enrollment and follow-up visits.The study was designed to test three primary hypotheses:Vitamin D deficiency is a risk factor for fibroid incidence and/or growth.Reproductive tract infections can increase risk of fibroid development.Genotypic variation in African ancestry may influence fibroid development directly, or through interaction with life-course risk factors.In addition, we collected extensive information to examine other exposures of interest, and our extra specimens can be used to test new hypotheses in the future.With this first prospective study of fibroid development, we aim to identify new preventative factors that could directly benefit women. We anticipate that the detailed data on fibroid development can be used to help design new interval treatment strategies to limit fibroid growth and thus reduce the need for the invasive treatments that remain the standard of care when first-line treatments fail.

  Study phs002513

• LCCC1122: Defining the Triple Negative Breast Cancer Kinome Response to GSK1120212

  In this study the investigators looked at adaptive reprogramming impact on the kinome when a MEK inhibitor called GSK1120212 (trametinib) was administered in a "window of opportunity" trial. GSK1120212 is not yet approved by the FDA for use in breast cancer patients. The investigators gave GSK1120212 for a short period of time (one week) to examine MEK and the other kinase expression in cancer cells both before and after the study drug is given. The investigators gave this drug for research purposes only. The length of time it was given is not intended to treat cancer. Recently researchers at UNC developed a process that can comprehensively profile the majority of the individual kinases in the kinome and examine the impact on kinase expression of kinase inhibitors (Duncan et al, Cell 2012, PMID: 22500798). This can tell us which kinases need to be concurrently blocked to augment responsiveness and prevent acquired resistance so that the investigators can design the best combinations of kinase blocking drugs for triple negative breast cancer. This is especially important for individuals with triple negative breast cancer (TNBC) because there are no targeted drugs available that can block molecules that affect tumor growth. The investigators believe that kinase-blocking drugs have the potential to be a more effective treatment for people with TNBC. In this recently published study (Zawistowski et al, Cancer Discovery 2017, PMID: 28108460), TNBC patients treated with trametinib for 7 days resulted in a transcriptional response characterized by significant reprogramming of the tyrosine kinome, and this adaptive bypass response in human tumors was found to be similar to that seen in preclinical models including TNBC cell lines and mouse xenografts. In this study we also examined whether reprogramming differed between TNBC molecular subtypes, finding that basal-like and claudin-low human TNBC cells and mouse tumor subtypes had different adaptive transcriptional responses to MEK-ERK inhibition. Mechanistically we found that genome-wide enhancer remodeling drove the adaptive transcriptional response, suggesting that epigenetic approaches to reprogramming may be more durable than kinase inhibitor polypharmacology.

  Study phs001405

• Separation of chronic myeloid leukemia stem cells from normal hematopoietic stem cells at single-cell resolution

  Chronic myeloid leukemia (CML) is a clonal disease, initiated and sustained by a subpopulation of CML stem cells (CML-SC) containing the BCR::ABL1 oncogene. Genetic markers that enrich for CML-SC have been identified, including CD26 being most specific. Genome sequencing analysis remain yet to be performed at single cell level in order to determine differences and heterogeneity in the genetic profile of CML-SC versus normal hematopoietic stem cells (HSC). Here we show that CD26 and CD33 separate CML-SC from normal HSC in freshly isolated bone marrow samples from newly diagnosed CML patients. DNA sequencing confirms that single CML-SC derived colonies are positive for BCR::ABL1 and harbor a recurrent set of patient-specific clonal somatic mutations across different CML-SC derived colonies. In contrast, marker-negative (CD26-CD33-) HSC from the same patients are negative for the BCR::ABL1 oncogene and do not carry recurrent, clonal mutation across different colonies. These results support the concept that CD26/CD33 expression separates genetically defined, clonal mutant CML-SC from normal HSC that carry individual sets of random mutations in CML patients. We provide whole exome DNA sequencing data for 23 clinical samples of CML-SC plus two buccal swipes derived normal samples. CML samples are comprised of 4 to 8 replicates from two patients, at diagnosis and after treatment. Single CML stem cells before treatment and single non-transformed HSC at remission were selected from bone marrow samples by FACS, according to genetic markers CD33+CD26+ at diagnosis and CD33+CD26-/CD33-CD26- at remission. WES libraries of colony forming assays derived CML-SC and HSC populations were prepared using Agilent SureSelect Human All Exon V6 kit and sequenced running 150 cycles (2x 75bp paired-end) on an Illumina NextSeq 500 platform. Following GATK best practices for somatic mutation calling, novel CML variants and random mutation events during remission phase were obtained.

  Study EGAS00001006904

• Center for Cancer Genomics (CCG) Cancers of Unknown Primary Project (CUPP)

  The Cancers of Unknown Primary Project (CUPP) aims to characterize difficult tumor types with the goal of determining future best treatment practices. NCI will utilize whole exome sequencing, copy-number variation, DNA methylation in conjunction with transcriptome sequencing to provide a comprehensive genomic landscape of Cancers of Unknown Primary (CUP). The samples will be processed and submitted for genomic characterization using pipelines and procedures established within the Center for Cancer Genomics (CCG).

  Study phs001801