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• The Bangladesh Environmental Enteric Dysfunction (BEED) Study

  Environmental enteric dysfunction (EED), a sub-acute inflammatory condition of the small intestinal mucosa of unclear etiology, has been associated with a variety of environmental exposures and host factors and is implicated in growth faltering. Linear growth faltering usually occurs within the first two years of life and in most of the cases is irreversible demanding early diagnosis for treatment to be successful. The objectives of 'The Bangladesh Environmental Enteric Dysfunction Study (BEED)' are to investigate role of EED in malnutrition, examine the biology of EED to identify common biological pathways for potential interventions, to validate a system for histological scoring for EED and test the effectiveness of nutritional interventions in improving the growth parameters in children with stunting and or EED. In Bangladesh, participants are recruited from two age groups; a child cohort and a malnourished an adult cohort. In addition, two control groups are recruited for comparison consisting of a) children that are undergoing endoscopy as a part of their clinical care at the University of Virginia Health system (UVAHS) and b) an adult well-nourished control group recruited from the Gastroenterology Outpatient Department of Dhaka Medical College and Hospital in Bangladesh. The description of the study design and procedures of the study can be obtained from Mahfuz M, Das S, Mazumder RN, et al., 2017, PMID: 28801442.

  Study phs001891

• Mate-pair sequencing of 12q-amplified osteosarcomas

  Mate-pair sequencing of 12q-amplified osteosarcomas for the detection of structural variants. This was carried out in order to study the structure of the chromosome 12q-amplicons and whether material from other chromosomes is also intertwined and amplified in a bid to further characterise these tumours beyond CDK4 and MDM2 amplification. Mate-pair data was also used to verify gene fusions detected with RNA-seq.

  Study EGAS50000000493

• GILD_ExomeSeq_PTNHL

  This study is meant to gain further knowledge in haematological cancers. Patients samples (mainly DNAs or PCR products) from haematolocical cancer patients will be sequenced, and the outputs will be correlated to their diagnosis and/or prognosis; the findings may also add more insight into the understanding of biology in this type of tumour. We will be sequencing Primary Testicular Lymphomas (PTL) to identify genetic drivers of this rare cancer

  Study EGAS00001001613

• Mitochondrial DNA mutations contribute to autism and also to the characteristics of mitochondrial disorders present in patients with autism spectrum disorders

  Intellectual disability (ID) is common among autism spectrum disorder (ASD) patients. Also, evidence from many fields of medicine has documented multiple non-CNS physiological abnormalities associated with ASD, suggesting that, in some individuals, ASD arises from systemic, rather than organ-specific abnormalities. Oxidative phosphorylation and mitochondrial dysfunction are frequently reported in ASD and ID and can be due to mitochondrial DNA mutations. Therefore, the objective of the study was to analyze the mitochondrial DNA of ID subjects with ASD (N=98) and without ASD (N=95) to identify putative pathogenic variants that could be associated with ID or ASD. The genome of reference used in this is study is NC_012920.1 (rCRS) (Homo sapiens mitochondrion).

  Study EGAS00001002750

• Mapping_gene_environment_interactions_in_macrophages

  Immune cells sense and respond to external stimuli such as pathogens and initiate an inflammatory response. Genetic variants altering the behaviour and responses of immune cells may inform the results of disease association studies and provide an insight into the regulation of immune response. Studies mapping quantitative trait loci (QTL) are usually performed in quiescent or naïve cells and therefore any variants with a condition-specific manner (e.g. those with an effect only detectable in a specific time-point after cell stimulation) are likely to remain undiscovered. So far, only a handful of studies have attempted to study QTL in multiple states and even on those studies the number of states has remained relatively low (<5). Only very recently Horst and colleagues published the largest study to date investigating the effect of host variable (e.g. age, sex, contraceptive use etc.) on protein levels in macrophages stimulated with 19 different conditions (Horst et al, 2016). This project aims to develop a high-throughput experimental platform to detect QTL in a large number of states using iPSC derived macrophages. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002268

• Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia

  Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL) is a recently described subtype of T-ALL characterized by a unique immunophenotype and genomic profile as well as a high rate of induction failure. Frequent mutations in cytokine receptor and JAK/STAT signaling pathways led us to hypothesize that ETP-ALL is dependent on JAK/STAT signaling. Here we demonstrate aberrant activation of the JAK/STAT pathway in ETP-ALL blasts relative to non-ETP T-ALL. Moreover, ETP-ALL showed hyperactivation of STAT5 in response to IL7, an effect that was abrogated by the JAK1/2 inhibitor ruxolitinib. In vivo, ruxolitinib displayed activity in 6/6 patient-derived murine xenograft models of ETP-ALL, with profound single-agent efficacy in 5 models. Ruxolitinib treatment decreased peripheral blast counts relative to pre-treatment levels and compared to control (P<0.01) in 5/6 ETP-ALL xenografts, with marked reduction in mean splenic blast counts (P<0.01) in 6/6 samples. Surprisingly, both JAK/STAT pathway activation and ruxolitinib efficacy were independent of the presence of JAK/STAT pathway mutations, raising the possibility that the therapeutic potential of ruxolitinib in ETP-ALL extends beyond those cases with JAK mutations. These findings establish the preclinical in vivo efficacy of ruxolitinib in ETP-ALL, a biologically distinct subtype for which novel therapies are needed.

  Study EGAS00001001146

• Patient-derived tumor organoids for personalized medicine in a rare case of hepatocellular carcinoma with neuroendocrine differentiation.

  We report the case of a 74-year-old man with a very rare subtype of hepatocellular carcinoma with neuroendocrine differentiation (HCC-NED). The patient presented with two independent tumors, a gastrointestinal stromal tumor in the stomach and a hepatocellular carcinoma in the liver. Both tumors were surgically removed in curative intent. Histopathological work-up of the liver tumor revealed poorly differentiated hepatocellular carcinoma (Edmondson-Steiner grade IV) with diffuse expression of neuroendocrine markers synaptophysin (SYP) and chromogranin (CHGA). Three months after resection, multifocal recurrence of the HCC with neuroendocrine differentiation (HCC-NED) was observed. In the meantime, tumor organoids have been generated from the resected HCC-NED and extensively characterized. Sensitivity to a number of drugs approved for the treatment of HCC or neuroendocrine carcinomas was tested in vitro. Based on their in vitro efficacy, etoposide and carboplatin were used as first line palliative combination treatment. Because genomic analysis revealed a NTRK1-mutation (kinase domain) and tumor organoids were sensitive to entrectinib, a pan-TRK inhibitor, the patient received entrectinib as second line therapy. After only two weeks, treatment had to be discontinued due to deterioration of the patient’s general condition. In conclusion, we demonstrate for the first time that preclinical drug testing using organoids is feasible in selected HCC cases.

  Study EGAS00001005887

• Exome sequencing of synchronous colorectal cancers

  Approximately 4% of colorectal cancer (CRC) patients have at least two simultaneous cancers in the colon. Due to the shared environment, these synchronous CRCs (SCRCs) provide a unique setting to study colorectal carcinogenesis. Understanding whether these tumors are genetically similar or distinct is essential when designing therapeutic approaches. We performed exome sequencing of 47 primary cancers and corresponding normal samples from 23 patients. Additionally, we carried out a comprehensive mutational signature analysis to assess whether tumors had undergone similar mutational processes and the first immune cell score analysis (IS) of SCRC to analyze the interplay between immune cell invasion and mutation profile in both lesions of an individual. The tumor pairs shared only few mutations, favoring different mutations in known CRC genes and signaling pathways, and displayed variation in their signature content. Two tumor pairs had discordant mismatch repair statuses. In majority of the pairs, IS varied between primaries. Differences were not explained by any clinicopathological variable or mutation burden.

  Study EGAS00001003474

• Whole Genome Sequencing on OCIAML-22

  Donor_OCIAML22_bulk: The donor (unsorted) that was used to generate OCI-AML22. OCI-AML22_bulk_1month_inVitro: The donor (unsorted) that was used to generate OCI-AML22 was expanded for 1 month in vitro, then sequenced. OCI-AML22_graft_CD34minus_WGS: The donor (unsorted) that was used to generate OCI-AML22 was expanded for 1 month in vitro, then injected in NSG-SGM3 mice. 21 weeks after injection, cells from 5 mice injected with 5 mice injected with 1475 cells per mice and 4 mice injected with 469 cells per mice were sorted. The human CD34- fraction was sequenced (CD45h+CD45m-7aad-annexinV-CD34-) OCI-AML22_graft_CD34positive_WGS: The donor (unsorted) that was used to generate OCI-AML22 was expanded for 1 month in vitro, then injected in NSG-SGM3 mice. 21 weeks after injection, cells from 5 mice injected with 5 mice injected with 1475 cells per mice and 4 mice injected with 469 cells per mice were sorted. The human CD34+ fraction was sequenced (CD45h+CD45m-7aad-annexinV-CD34+)

  Study EGAS00001006513

• Genomic sequencing of Pediatric Rhabdomyosarcoma

  Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood accounting for approximately 350 newly diagnosed cases yearly in the United States. With the development of multimodal chemotherapy regimens, relapse-free survival rates have improved to 70-80% in patients with localized disease albeit with significant toxicity. Unfortunately, despite aggressive treatment, patients with metastatic or recurrent disease continue to suffer from high mortality. Further characterization of the genetic events underlying this tumor type is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. In a collaborative effort between the National Cancer Institute, the Children's Oncology Group, and the Broad Institute, we use a combination of whole-genome and whole-exome sequencing to characterize the landscape of somatic alterations in 147 tumor/normal pairs.

  Study phs000720