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• Somatic mutation burden and copy-number variation analysis in neurofibromatosis type 1-associated plexiform neurofibromas

  Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from biallelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time, e.g., there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0 - 8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.

  Study phs001403

• Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated After Starting Hu14.18-IL2 Predicts Outcome

  Background: We analyzed whole transcriptome sequencing in tumors from 23 patients with stage III or IV melanoma from a pilot trial of the anti-GD2 immunocytokine, hu14.18-IL2, to identify predictive immune and/or tumor biomarkers in melanoma patients at high risk for recurrence. Methods: Patients were randomized to receive the first of 3 monthly-courses of hu14.18-IL2 immunotherapy either before (Group A) or after (Group B) complete surgical resection of all known disease. Tumors were evaluated by histology and whole transcriptome sequencing. Results: We report here that tumor infiltrating lymphocyte (TIL) levels directly associate with relapse-free survival (RFS) and overall survival (OS) in resected tumors from Group A, where early responses to the immunotherapy agent could be assessed. TIL levels directly associated with a previously reported immune signature which associated with RFS and OS, particularly in Group A tumors. In Group A tumors there were decreased cell cycling gene RNA transcripts, but increased RNA transcripts for repair and growth genes. We found that outcome (RFS and OS) was directly associated with several immune signatures and immune-related RNA transcripts and inversely associated with several tumor growth-associated transcripts, particularly in Group A tumors. Most of these associations were not seen in Group B tumors. Conclusion: We interpret these data to signify that both immunologic and tumoral cell processes, as measured by RNAseq analyses detected shortly after initiation of hu14.18-IL2 therapy are associated with long term survival and could potentially be used as prognostic biomarkers in tumor resection specimens obtained after initiating neoadjuvant immunotherapy. Note: RNA sequences and expression data can be found at NCBI GEO GSE133713

  Study phs001947

• Genomic Analysis of Mycosis Fungoides and Sézary Syndrome Identifies Recurrent Alterations in TNFR2

  Mycosis Fungoides (MF) and Sézary Syndrome (Sz) comprise the majority of Cutaneous T-Cell Lymphoma (CTCL) cases and are characterized by clinical heterogeneity. This array of symptoms includes skin patches, plaques and tumors as well as blood involvement and erythroderma. Because the genetic basis of CTCL is still poorly understood, we performed whole-exome sequencing on 11 MF/Sz samples and their matched, normal control DNA. Upon analyzing this data, we distilled a list of an additional 494 genes to be sequenced at depth. The majority of these 494 genes were sequenced in the exons alone, however, for a small subset of these genes we sequenced the entire genomic locus in search of structural variation events. This 494 gene targeted resequencing effort was performed upon 72 patients with MF/Sz and their matched, normal control DNA. An additional 5 MF/Sz and matched, normal DNA samples underwent whole genome amplification (WGA) prior to library preparation, which appears to have introduced mutations into these samples, however we also include them here. We additionally include 10 MF/Sz samples without a matched, normal control samples, 1 of which underwent WGA. In addition to primary disease samples, we also performed targeted resequencing on 4 CTCL cell lines (HH, MyLa, SeAx and Hut78) as well as on H9 cells (a subclone of Hut78 cells) and Jurkat cells, a T-ALL derived cell line that was used as an experimental system for our work. In sum, this data deposition includes exome and/or targeted resequencing from 92 individuals with 192 samples submitted.

  Study phs000913

• Longitudinal Study of Immune Mediated Disorders After Allogenic Hematopoietic Cell Transplantation (HCT)

  Allogeneic hematopoietic cell transplantation (HCT) is the only known curative option for many hematologic disorders. After transplantation, many patients develop immune mediated disorders that may be life-threatening. Post-HCT immune mediated disorders are rare relative to other diseases but the prototype of graft versus host disease (GVHD) develops in 30-70% of patients. The morbidity and mortality associated with these HCT-associated immune mediated disorders are major barriers to successful use of transplantation to cure rare hematologic malignancies such as leukemia, lymphoma, multiple myeloma, myelodysplastic/myeloproliferative syndromes amongst other diseases. The purpose of this study is to characterize and more completely define the onset and course of immune mediated disorders after allogeneic HCT, focusing on participants who develop cutaneous sclerosis, bronchiolitis obliterans syndrome (BOS), late acute graft-vs.-host disease (GVHD), and chronic GVHD. Of the participants undergoing allogeneic hematopoietic cell transplantation (HCT), can we, the researchers better identify who will develop immune-mediated disorders, what types of disorders participants will have, and whether these disorders will be severe or respond to currently available therapies? This is a longitudinal study of 1118 individuals (1081 adults and 100 children). Those participating in this study will be evaluated over a 3 year period at 9 study sites. Participants will be enrolled pre-transplant, or up to day 121 post transplantation. This wide enrollment window will allow sites to use recruitment methods that are most efficient at their institutions. At least 2 years of follow-up will ensure an adequate sample size, and sufficient time for observation of the full spectrum of immune mediated disorders. The data of 1023 individuals have been submitted to dbGaP.

  Study phs001331

• NHLBI TOPMed: Genetics of Cardiometabolic Health in the Amish

  The Amish Complex Disease Research Program includes a set of large community-based studies focused largely on cardiometabolic health carried out in the Old Order Amish (OOA) community of Lancaster, Pennsylvania (http://medschool.umaryland.edu/endocrinology/amish/research-program.asp). The OOA population of Lancaster County, PA immigrated to the Colonies from Western Europe in the early 1700's. There are now over 30,000 OOA individuals in the Lancaster area, nearly all of whom can trace their ancestry back 12-14 generations to approximately 700 founders. Investigators at the University of Maryland School of Medicine have been studying the genetic determinants of cardiometabolic health in this population since 1993. To date, over 7,000 Amish adults have participated in one or more of our studies. Due to their ancestral history, the OOA may be enriched for rare variants that arose in the population from a single founder (or small number of founders) and propagated through genetic drift. Many of these variants have large effect sizes and identifying them can lead to new biological insights about health and disease. The parent study for this WGS project provides one (of multiple) examples. In our parent study, we identified through a genome-wide association analysis a haplotype that was highly enriched in the OOA that is associated with very high LDL-cholesterol levels. At the present time, the identity of the causative SNP - and even the implicated gene - is not known because the associated haplotype contains numerous genes, none of which are obvious lipid candidate genes. A major goal of the WGS that will be obtained through the NHLBI TOPMed Consortium will be to identify functional variants that underlie some of the large effect associations observed in this unique population.

  Study phs000956

• Modifier Genes in 21-hydroxylase Deficiency

  CAH is a genetic steroidogenesis disorder. The most common form, 21OHD, leads to cortisol deficiency and, in turn, an excess of androgen, a hormone that promotes the development and maintenance of male sex characteristics. As a result of this androgen excess, prepubescent males and newborn, prepubescent, and grown females exhibit mature masculine characteristics. The symptoms and severity of 21OHD vary among individuals with the disease and in adults versus children. The reasons for these differences are not yet known. Current therapy for 21OHD consists of administration of glucocorticoids to replace cortisol and suppress excessive pituitary function. With more information about what genes or factors contribute to the severity of 21OHD, researchers may be able to better treat children and adults with the disease. This study will examine participants' DNA to determine what other genes may affect the severity of 21OHD and may make the disease milder in adults than in children This is a 3-day inpatient study. Once eligibility is confirmed through physical exam and blood analysis, eligible participants are admitted to the study site in the morning on the first study day. A blood sample is taken and participants receive one 10-mg pill of hydrocortisone. Heart rates and blood pressures are taken every 4 hours throughout the day. In the morning of Day 2, a blood sample will be obtained and a 24 hour urine collection will begin. On the morning of Day 3, another blood sample is obtained. Participants then receive intravenous cosyntropin, a synthetic form of a hormone that the body makes. About 1 hour after this, participants provide a final blood sample. Participants receive a pill of hydrocortisone prior to the end of the study.

  Study phs001313

• Non-coding RNAs Activated by the Wnt/Beta-catenin Signaling Pathway in Hepatoblastoma

  Hepatoblastoma (HB) is the most common pediatric liver tumor, affecting mostly children under 3 years of age. This rare tumor represents 1% of all pediatric cancers. Genetic studies have shown that HB is characterized by high frequency mutations of the CTNNB1 gene encoding beta-catenin (around 75%) and relative genomic stability. Here we have analyzed the transcriptional profile of 21 HBs compared to matched non-tumor livers by Cap Analysis of Gene Expression (CAGE), which provides accurate and quantitative profiling of all transcripts. CAGE analysis revealed strong upregulation of known Wnt target coding genes in most tumors analyzed, consistent with previous transcriptomic studies. To better define the Wnt-dependent transcriptional landscape of HB, we integrated CAGE data with TCF4 ChIP-seq data from a CTNNB1-mutated cancer cell line and with the FANTOM5 genomic coordinates of TCF/LEF binding motifs. Both TCF/LEF binding motifs and ChIP-seq peaks were strongly enriched in the immediate upstream region, not only for protein-coding genes, but also for non-coding transcripts. Among the selected 112 top Wnt target genes at FDR<1.0E-6 and fold change>8, we found clear over-representation (66%) of distant transcription start sites (TSSs) representing lncRNAs and enhancer RNAs, which raises the question of their role in HB pathogenesis. Analysis of the 112 promoters using CAGEd-oPOSSUM confirmed the predominant involvement of Tcf/Lef transcription factors, together with HNF4G, GATA2, Sox3 and Ets-related genes. Finally, the 112 Wnt target signature defined 3 tumor subclasses, T1, T2 and T3, characterized by progressive alteration of the non-coding part of the transcriptome and significant differences in clinical behavior.

  Study phs001433

• Mitochondrial DNA deletion detection in POLG patients

  Accumulation of deletions in the mitochondrial genome is a pathological hallmark of both aging and a broad range of neurometabolic disorders. Prior mtDNA deletion studies have been limited by reliance upon either long range PCR or NGS strategies that target specific regions of the mitochondrial genome. We developed an ultrasensitive high throughput sequencing process (LostArc) to identify and quantify all deletions in circular DNA molecules while minimizing interference from linear DNA and PCR artefacts. We applied this process to skeletal muscle biopsies from 19 unaffected individuals (aged 17 to 93 years) and from 22 patients with heritable mitochondrial disease (17 to 80 years) bearing pathogenic variants in POLG, the nuclear gene encoding the catalytic subunit of the mitochondrial replicative DNA polymerase ɣ (Pol ɣ). To our astonishment, LostArc revealed 35 million mtDNA deletions with ~470,000 unique deletion spans. This unprecedented volume of data enabled detailed and highly informative bioinformatics analyses. We show that ablation of mtDNA is sufficient to explain skeletal muscle phenotypes associated with aging and POLG-derived disease, with a clear threshold separating symptomatic and asymptomatic individuals. Unsupervised hierarchical clustering and principle component analysis reveal distinct age- and disease-correlated deletion patterns that implicate DNA replication by Pol ɣ in the formation of mtDNA deletions. Deletion patterns also point to active mtDNA replication but little or no purifying selection against deleted mtDNA by mitophagy in postmitotic muscle fibers. Monte Carlo simulations of varied hypotheses for deletion formation, based in part on competing models of mtDNA replication, suggest the observed patterns are most consistent with deletions initiated by replication fork stalling during strand displacement mtDNA synthesis. Note that sequence data for HEK293 can be found under BioProject PRJNA642884.

  Study phs002052

• Addictions: Genotypes, Polymorphisms, and Function/Human Genetic Correlates of Addictive Diseases

  Drug addiction continues to be a major medical and social problem. It is estimated that one million or more persons in the United States are currently addicted to heroin or prescription opioids, with millions more worldwide. Cocaine addiction and alcohol dependence are frequent comorbid conditions in persons with heroin/opioid dependence in addition to being major primary addictions. Many studies over the past thirty years have shown that these drugs disrupt physiologic systems, and that these disruptions may contribute to drug addiction and alcohol dependence and to relapse to drug or alcohol abuse following withdrawal and abstinence. Clinical observations suggest that individuals differ in their response to heroin, cocaine, and alcohol; however, little is known about specific underlying hereditary genetic factors which might influence individual susceptibility to the addictive properties of these substances. Studies also suggest that both common and distinct heritable factors account for the genetic variance in the susceptibility to the separate addictive diseases. We hypothesize that there is a heritable as well as environmental basis for the acquisition and persistence of, and relapse to, specific addictive diseases. Using samples from individuals without and with opioid and other specific drug dependence diagnoses and psychiatric comorbidities, genetic analyses will be used to determine association and linkage. All study subjects will be extensively characterized with respect to the addictive diseases, medical history, family medical addictive disease history; psychiatric comorbidity, and psychological profile, as well as ethnic/cultural background. A better understanding of the consequences of genetic contributions with respect to protection from, or susceptibility to, heroin/opioid addiction and related codependencies and comorbid conditions, could have enormous importance in both prevention and treatment of this problem.

  Study phs001109

• Gene mutation and rescue in congenital diaphragmatic hernia

  Congenital Diaphragmatic Hernia (CDH) is a common and life-threatening malformation. The most common phenotype is left-sided posterolateral (Bochdalek-type) hernia accompanied by pulmonary hypoplasia. Due to the high mortality, most of the cases have no family history for CDH. The rare presumed Mendelian instances of CDH have the potential to be extremely informative about the molecular mechanisms generating this phenotype. Three multiplex families were deemed meritorious for study by whole exome sequencing: Parents who were 1st cousins gave birth to 2 children with CDH (one of whom also had cleft lip and palate), both now deceased. A DNA sample was available from one child. We proposed to perform a SNP array to identify regions of homozygosity by descent and intersect these regions with variants detected on exome sequencing. This effort has led to the identification of 3 confirmed variants. We are determining which if any are expressed in the primordial developing diaphragm and are also using bioinformatic approaches to determine which of these candidates interact with known CDH genes. This non-consanguineous couple gave birth to 2 affected boys with an identical and lethal CDH phenotype (consisting of diaphragmatic hernia, epigastric hernia, and facial dysmorphism) and one healthy boy. We predicted X-linked inheritance and findings from X chromosome microsatellite marker analysis are consistent with this. Accordingly, we are focusing on sequence variants mapping to the X chromosome. We have identified a single candidate gene and confirmed that the variant follows an X-linked pattern of inheritance in all family members. Expression studies are underway. These affected males are second cousins. By virtue of their position in the pedigree, we predicted an inheritance pattern consistent with X-linked inheritance. Data from WES and microsatellite marker analysis are currently being integrated.

  Study phs000485