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• Rare Mendelian Disease in Old Order Amish and Mennonite Patients

  The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data.

  Study phs000623

• Immune Response to Life-Threatening Respiratory Infections in Children and Young Adults

  This is a cross sectional study describing age-related differences in the nasal mucosal immune response to SARS-CoV-2. We collected nasal mucosal samples from six groups: healthy children, children infected with SARS-CoV-2, children infected with respiratory syncytial virus, children infected with influenza virus, healthy adults, and adults infected with SARS-CoV-2. Samples were obtained by mucosal scrape biopsy of the inferior turbinate using a sterile plastic curette. We performed bulk RNA-sequencing to obtain gene expression data. Clinical data was extracted from the electronic health record including: demographics, medical history, clinical presentation, duration of symptoms, intensive care unit admission, hospital and intensive care unit length of stay, type and duration of respiratory support at sample collection and peak illness. Our analysis described the host response to SARS-CoV-2 in the nasal mucosa in children and adults and compared it to the host response to respiratory syncytial virus and influenza virus.

  Study phs002579

• Direct genetic transformation bypasses tumor-associated DNA methylation alterations

  Tumors represent dynamically evolving populations of mutant cells, and many advances have been made in understanding the biology of their progression. However, key unresolved questions remain about the conditions that support their initial transformation, which cannot be easily captured in patient populations but are instead modeled using transgenic cellular or animal systems. Here, we used extensive patient atlas data to define common features of the tumor DNA methylation landscape as they compare to healthy human cells and used this benchmark to screen 21 engineered human and mouse models for their ability to reproduce these patterns. Notably, we find that genetically induced cellular transformation can trigger global changes in DNA methylation levels that are consistent with extensive proliferation but rarely recapitulate the widespread de novo methylation of Polycomb targets as found in clinical samples. Our results raise pertinent questions about the relationship between genetic and epigenetic aspects of tumorigenesis and provide an important molecular reference for evaluating existing as well as newer tumor models.

  Study EGAS50000000902

• Dual inhibition of FLT3 and BCL-2 is effective in preclinical models of BCL11B-activated lineage ambiguous leukemia

  Aberrant activation of BCL11B (“BCL11B-a”) defines a subtype of lineage ambiguous leukemias with T-lymphoid and myeloid features, co-occurring activating FLT3 mutations, and a stem/progenitor immunophenotype and gene expression profile. As with other lineage ambiguous leukemias, optimal treatment is unclear and there are limited targeted therapeutic options. Here, we investigated the efficacy of BCL-2 and FLT3 inhibition with venetoclax and gilteritinib, respectively, in preclinical models of BCL11B-a leukemia. Despite variation in response to single agent therapies, the combination of venetoclax plus gilteritinib was highly effective in all models evaluated. BH3 profiling and single cell RNA-seq analysis suggests that resistance to venetoclax and/or gilteritinib monotherapies is due to the tumor-intrinsic activity of BCL-xL and/or MCL-1 prior to drug treatment. These data support clinical evaluation of venetoclax in combination with gilteritinib in BCL11B-a lineage ambiguous leukemias.

  Study EGAS50000000978

• Whole genome sequencing of six ethnic groups from Burkina Faso, Cameroon, and Tanzania

  We conducted low-coverage (~10x) sequencing of six ethnic groups from three malaria-endemic countries in sub-Saharan Africa, with the aim of characterising genetic diversity and improving imputation performance for genotyped samples in these populations. This data is part of a pre-publication release and is available under managed access. Please see https://www.malariagen.net/data/terms-use/human-gwas-data for more information on MalariaGEN data access policies. The purpose of the project was to support the discovery and understanding of genetic variants that influence human disease. Specifically defined goals were: a. the discovery of single nucleotide variants at frequencies of 1% or higher in diverse populations, b. even more comprehensive discovery (variants down to frequencies of 0.1 - 0.5%) in functional gene regions, and c. discovery of structural variants, such as copy number variants, other insertions and deletions, and inversions, including sequence-level understanding of breakpoints.

  Study EGAS00001003648

• Spatial genomic heterogeneity in multiple myeloma revealed by multi- region sequencing

  The bone-marrow (BM) containing skeletal system is the reservoir of Multiple Myeloma (MM), the malignant counterpart of antibody-secreting plasma cells. To gain insight into its spatial clonal architecture, we performed multi-region whole-exome sequencing of radiology-guided fine-needle aspirates from 51 MM patients. We found spatial genomic heterogeneity in a substantial proportion of cases including bi-allelic inactivation of tumor suppressors and mutations affecting cancer genes. The amount of heterogeneous mutations associated with the size of focal tumor lesions in whole body imaging consistent with focal outgrowth of highly advanced clones. In conclusion, our results support the regional initiation of transformation processes leading to high-risk disease as well as the pre-existence of key driver events in restricted areas. As such, our study does not only provide new insights in the underlying biology of MM progression but also has considerable implications for standard diagnostic approaches in the clinic.

  Study EGAS00001002111

• A Genomics-Based Classification of Human Lung Tumors

  We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

  Study EGAS00001000647

• Hi-C dataset for testicular germ cell tumour GWAS risk loci, as described in the Oncoarray Litchfield et al. 2016 paper.

  Genome-wide association studies (GWAS) have transformed our understanding of testicular germ cell tumour (TGCT) susceptibility but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, approximately doubling the number of known TGCT risk loci to 44. By performing in-situ Hi-C in TGCT cells, we establish a network of physical interactions between all 44 TGCT risk SNPs and candidate causal genes. Our findings reveal widespread disruption of developmental transcriptional regulators as a basis of disease susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis1. Defective microtubule assembly and dysregulation of KIT-MAPK signalling also feature as recurrently disrupted pathways. Our findings support a polygenic model of disease risk and provide insight into the biological basis of TGCT.

  Study EGAS00001001930

• Circulating tumor cells for comprehensive and multiregional non-invasive genetic characterization of multiple myeloma (arrays set)

  Multiple myeloma (MM) patients undergo repetitive bone marrow (BM) aspirates for genetic characterization. Circulating tumor cells (CTCs) are detectable in peripheral blood of virtually all MM cases and are prognostic, but their applicability for non-invasive screening has been poorly investigated. Here, we used next-generation flow cytometry to isolate matched CTCs and BM tumor cells from 42 patients and compare their genetic profile. In 8 cases, tumor cells from extramedullary plasmacytomas were also sorted and whole-exome sequencing performed in the three spatially-distributed clones. Noteworthy, ≥84% mutations present in BM and extramedullary clones were detectable in CTCs. Concordance between BM tumor cells and CTCs was high for chromosome arm-level copy-number alterations (≥94%) though not for translocations (43%). All high-risk genetic abnormalities except one t(4;14) were detected in CTCs whenever present in BM tumor cells. Altogether, these results support CTCs for non-invasive risk-stratification of MM patients based on their numbers and genetic profile.

  Study EGAS00001004314

• Oncogenic cooperation in a human de novo T-ALL model

  We previously modelled T-cell acute lymphoblastic leukemia (T-ALL) by over-expressing four oncogenes (activated NOTCH1, LMO2, TAL1, and BMI1) in healthy human umbilical cord blood cells through lentiviral transduction (Kusakabe et al, Nat Commun 10, 2913 (2019). https://doi.org/10.1038/s41467-019-10510-8). We have now tested individual effects of the four oncogenes by transducing human cells with all possible combinations of one, two, three, and four oncogenes. We also tested the effects of additional known T-ALL oncogenes including HOXA9, LYL1, MEF2C, NXK2.1, TLX1, and TLX3. In addition to culture in vitro on OP9-DL1 feeders, we also injected transduced cells into immunodeficient NSG mice. We observed differing abilities of the various oncogene combinations to support growth in vitro and frank leukemia in vivo. This study includes RNA-seq data from samples of transduced cells cultured in vitro as well as cells harvested from clinically moribund mice after development of leukemia in vivo.

  Study EGAS00001006055