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• Genome-wide evaluation of the maturation of the immune response to the tuberculin skin test from day 2 to day 7

  The tuberculin skin test (TST) is a standardised human challenge model to evaluate the immune response to Mycobacterium tuberculosis (Mtb) antigens in vivo. To study the temporal evolution of the TST, we recruited healthy volunteers with evidence of peripheral blood Mtb reactive T cells, to undergo a TST in each arm that was sampled on day 2 at one site and on day 7 at the contralateral site on day 7. Genome-wide TST transcriptomes at day 2 and day 7 were defined by differential gene expression compared to transcriptomes from the site of control saline injections performed in a separate subset of volunteers.

  Study EGAS50000000822

• Origins and timing of emerging lesions in advanced renal cell carcinoma

  Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in ~10% of cases and is thought to represent more advanced disease. RCC with VTT and distant metastasis provides unique opportunities to examine the origins and relative timing of tumor lesion emergence and to identify molecular correlates with disease state. We performed multi-region exome and RNA sequencing analysis of a clinical cohort of 16 RCC patients with VTT, with eight patients also having sequenced metastasis, to examine which genomic alterations, biological pathways, and evolutionary processes contribute to VTT and metastasis, and to ask whether metastasis typically arises directly from VTT or is independent of VTT.

  Study EGAS00001005897

• ARST17B2-Q Germline and Somatic Genetic Landscape of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. While these malignancies display aberrant myogenic differentiation, relatively little is known about genetic susceptibility to RMS, or how genetic variants influence subsequent somatic events and may be used in risk stratification strategies. A small percentage of cases are associated with mutations in TP53 (Li-Fraumeni syndrome), HRAS (Costello syndrome), and PTCH1 (nevoid basal cell carcinoma syndrome/Gorlin syndrome), suggesting the genetic origins of childhood RMS. In spite of this, little work has been done to characterize genetic susceptibility to this malignancy. We plan to leverage samples collected as part of D9902 to conduct one of the largest germline genomic studies of RMS. We anticipate that once genetic associations are identified, researchers can use the information to develop better strategies to detect, treat, and prevent childhood RMS.

  Study phs003192

• Accurate Immune Repertoire Sequencing Reveals Malaria Infection Driven Antibody Lineage Diversification in Young Children

  This study describes a novel Immune Repertoire Sequencing technique, termed Molecular Identifier Clustering-based Immune Repertoire Sequencing (MIDCIRS), to reduce sequencing error while maintaining extremely high coverage and applies this technique to investigate the differential immune response to malaria between infants and toddlers. Despite a lower somatic hypermutation load, we found an unexpectedly high level of competency within the infant antibody repertoire, particularly the ability to diversify B cell clonal lineages upon acute infection. Detailed clonal lineage analysis encompassing lineages containing sequences from both pre- and acute malaria timepoints revealed an increase in somatic hypermutations upon acute infection. Further analysis on pre-malaria memory B cell containing lineages in toddlers who had previously been exposed to malaria provides evidence for the capacity of memory B cells to continue to mutate and isotype switch.

  Study phs001209

• Somatic L1 Retrotransposition in Colorectal Tumors

  The purpose of this study is to ascertain the locations of somatic LINE-1 retrotransposition events in human colon tumor samples by pooling multiple tumor samples from different patients and performing a targeted resequencing assay (Ewing and Kazazian, Genome Research 2010) to sequence the 3' flanking regions of all insertions in the pooled sample. The result is compared to the result of applying the same method to pooled normal samples from the same patients as were used in the pooled tumor sample and selecting sites that show an insertion in the tumor but not in the normaltissue and do not correspond to any known non-reference LINE-1 insertion allele. The selected sites are then validated by site-specific PCR and capillary sequencing to confirm that they represent LINE-1 insertions and to obtain breakpoint sequences.

  Study phs000536

• The Epilepsy Phenome/Genome Project

  The Epilepsy Phenome/Genome Project (EPGP) is a large-scale, international, multi-institutional, collaborative research project, sponsored by the National Institute of Neurological Disorders and Stroke, designed to understand the genes that cause common and rare epilepsies. The overall goal of EPGP is to collect detailed, high quality phenotypic (i.e., characteristics of individuals, from the molecular level to the whole person) information on persons with epilepsy and to compare the phenotypic information with genomic information. 27 clinical centers enrolled more than 4,100 participants of families with epilepsy. EPGP will provide a resource that may lead to many discoveries related to the diagnosis and treatment of epilepsy, including the eventual development of new therapies based on a better understanding of causes of the disorder. Documents and questionnaires that provide context to the variables and measurements available through the current study, are available for download from EPGP: Download EPGP Forms.

  Study phs000742

• UCSF Center for Reproductive Health (CRH) Research Bank

  The purpose of this study is to provide a reference profile of small extracellular RNAs in body fluids. These samples were originally obtained in a study that had a different purpose. The purpose of the original study was to add excess biological materials during the course of IVF treatment to a tissue bank. These biological materials included follicular fluid (the liquid that comes out of the ovary with the egg), granulosa cells (cells that surround the egg and help it grow), and other biological materials that help eggs, sperm, and embryos stay healthy and grow outside the body. These banked specimens would allow researchers to learn more about infertility and how to treat it, including studying how to identify the healthiest eggs, sperm, and embryos and how to help them stay healthy and grow.

  Study phs001695

• CRLF2_sequencing_project_

  I hope to gain insight into novel genetic aberrations present in these patients that will highlightimportant pathways that are involved in this subtype of leukaemia. It would be interesting to see ifthe mutations and pathways that are activated are consistent between the patients, or differencesare observed dependent upon whether the patient has the translocation or the PAR1 deletion. Ofnote is the high association with either numerical gains of chromosome X or numerical/structuralabnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. Ihope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. Byincluding the three patients that are normal for CRLF2, but have consistent genetic abnormalitiesfound in the experimental cohort, I expect to find genetic differences between these two groupsthat will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000080

• CRLF2_sequencing_project_Exomes

  I hope to gain insight into novel genetic aberrations present in these patients that will highlight important pathways that are involved in this subtype of leukaemia. It would be interesting to see if the mutations and pathways that are activated are consistent between the patients, or differences are observed dependent upon whether the patient has the translocation or the PAR1 deletion. Of note is the high association with either numerical gains of chromosome X or numerical/structural abnormalities of chromosome 21 (Down syndrome, iAMP21) in patients with CRLF2 deregulation. I hope to find abnormalities linking chromosomes X and 21 to CRLF2 deregulation in BCP‐ALL. By including the three patients that are normal for CRLF2, but have consistent genetic abnormalities found in the experimental cohort, I expect to find genetic differences between these two groups that will help us to identify novel molecular targets specific to CRLF2 deregulation.

  Study EGAS00001000081

• Field_effect_of_healthy_and_diseased_livers_WGS

  Recent work in the Campbell group has revealed somatic mutations present in normal, non-cancerous human skin. A subset of the mutations conferred selective advantages to the host cells, leading to clonal expansions and raising the risk for future cancer development. Capturing such somatic mutations in normal tissue is important to advance our understanding about carcinogenesis and could provide prospective medical insights. In this project, our goal is to detect somatic mutations in normal (pre-cancerous) liver tissue. Using Laser Microdissection technology, we will dissect individual liver lobules from patient samples and submit these to sequencing. For each patient sample, we aim to sequence multiple lobules to characterise the mutagenic burden. Samples will be taken from patients with different liver disease aetiologies, including alcoholism and obesity, with a view on distinguishing the prevalent mutation types occurring in each disease context. We will perform both whole genome and targeted sequencing, initially using the WTSI cancer panel. Later we aim to use a novel bait set that captures both cancer genes as well as genes relevant to the non-cancerous samples (ie. genes implicated in hereditary disorders, immune sequences).

  Study EGAS00001002413