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• HipSci___Whole_Exome_sequencing___PID

  The HipSci project brings together diverse constituents in genomics, proteomics, cell biology and clinical genetics to create a UK national iPS cell resource and use it to carry out cellular genetic studies. In this sub-study we perform whole exome sequencing using Agilent whole exome pulldown method on iPS cells generated from skin biopsies or blood samples from rare disease patients diagnosed with blood and platelet disorders

  Study EGAS00001001983

• Exome sequencing of Fibromyalgia patients

  Fibromyalgia is a complex disorder characterized by increased sensitivity to pain and extreme tiredness. It affects mostly women, and its causes are unknown. In this study we have performed exome sequencing of 87 fibromyalgia cases, including some sibling pairs, to perform rare variant association analysis and identify fibromyalgia risk factors. A few of the included samples have been also included in a previous GWAS study.

  Study EGAS00001003826

• Evolution of the African pygmy phenotype

  The evolutionary history of the human ‘pygmy’ phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (East Central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses we computed the haplotype-based iHS statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (West Central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.

  Study EGAS00001000908

• Characterization of Immune Evasion in Merkel Cell Carcinoma

  Merkel cell carcinoma (MCC) is a rare, neuroendocrine skin carcinoma that is caused by the Merkel cell polyomavirus (MCPyV) in 80% of cases and by ultraviolet (UV) damage in 20% of cases. MCC should theoretically elicit a strong cytotoxic T cell response due to the high neoantigen and viral antigen burden in MCPyV- and MCPyV+ MCC, respectively. However, MCC often escapes immune recognition and is associated with very poor prognosis at advanced stages. To systemically identify mechanisms of immune evasion in MCC, we established 11 robust MCC lines from either primary tumors or patient-derived xenografts (7 MCPyV+ and 4 MCPyV-). We then characterized these tumors and cell lines by whole exome sequencing (WES), RNA-sequencing, scRNA-sequencing, ATAC-seq, and whole genome bisulfite sequencing (WGBS). We also studied MCC transcriptional subtypes, utilizing bulk and scRNA-sequencing datasets of patient-derived tumors and cell lines to investigate profiles of neuroendocrine gene expression. The genes linked below define either a neuroendocrine or a non-neuroendocrine phenotype presence within MCC tumors.

  Study phs002260

• Aberrant Oligoclonal Hematopoiesis in Remission AML and Relapse from Rare Cells Genomically Resembling Leukemic Blasts

  Acute myelogenous leukemia (AML) is a hematological malignancy that often responds well to initial treatment in which patients achieve a complete remission (CR). Nevertheless, most patients will relapse after achieving a CR, which is often fatal. This minimal residual disease (MRD) that remains after CR is likely the source of relapse and so improved measurement and characterization of these residual cells is critical. Employing droplet digital PCR (ddPCR), we were able to measure mutated alleles of many recurrently mutated genes in bone marrow samples acquired during CR from AML patients at levels as low as 0.002% variant allele frequency. Most of these gene mutations persisted in CR but at very variable and gene-dependent levels. Most AML cases involved residual aberrant oligoclonal hematopoiesis, and rare cell populations (as few as 1 in 15,000) were detected that were genomically similar to the AML blast populations at that dominated at diagnosis and were fully clonally represented at relapse. From a clinical perspective, the mutant allele frequency correlated closely with relapse-free and overall survival.

  Study phs001408

• Dynamics of neoantigen landscape during immunotherapy

  Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in non-small cell lung cancer patients after initial response to immune checkpoint blockade with anti-PD1 or anti-PD-1/anti-CTLA4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T cell expansion in autologous T cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations and were associated with changes in T cell receptor clonality. These analyses provide insights into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for development of immune therapies that target tumor neoantigens.

  Study EGAS00001002704

• Genome Landscape of High-Grade Serous Ovarian Cancer

  Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.

  Study EGAS00001000397

• Spatial Transcriptomics on prostate cancer heterogeneity

  Intratumor heterogeneity is one of the biggest challenges in cancer treatment today. Here we investigate tissue-wide gene expression heterogeneity throughout a multifocal prostate cancer using the spatial transcriptomics (ST) technology. Utilizing a novel approach for deconvolution, we analyze the transcriptomes of nearly 6750 tissue regions and extract distinct expression profiles for the different tissue components, such as stroma, normal and PIN glands, immune cells and cancer. We distinguish healthy and diseased areas and thereby provide insight into gene expression changes during the progression of prostate cancer. Compared to pathologist annotations, we delineate the extent of cancer foci more accurately, interestingly without link to histological changes. We identify gene expression gradients in stroma adjacent to tumor regions that allow for re-stratification of the tumor microenvironment. The establishment of these profiles is the first step towards an unbiased view of prostate cancer and can serve as a dictionary for future studies.

  Study EGAS00001003001

• BIRC5 Upregulation Enhances DNMT3A-Mutant T-ALL Cell Survival and Pathogenesis

  The goal of this study was to determine how patients with T-ALL who have DNA methyltransferase 3 alpha (DNMT3A) mutations develop resistance to therapy. Since DNMT3A is a methyltransferase, we examined the effect of those mutations on epigenetic regulation using whole genome bisulfite sequencing (WGBS). We also assessed any changes in gene expression using RNA-sequencing. We found that T-ALL patients with DNMT3A mutations are resistant to apoptosis and some chemotherapies. WGBS showed that DNMT3A mutated patients clustered together by their epigenetic profile, which was associated with hypomethylation at TERT and HOX genes. RNA sequencing identified differences in JAK/STAT signaling.

  Study phs003623

• Host genotyping data from Dutch adult bacterial meningitis patients and linked bacterial genome sequences

  Streptococcus pneumoniae is a common nasopharyngeal colonizer, but can also cause life-threatening invasive diseases such as empyema, bacteremia and meningitis. Genetic variation of host and pathogen is known to play a role in invasive pneumococcal disease, though to what extent is unknown. This study includes 1146 samples of host genotyping data (genotyped and imputed) from Illumina Omni arrays. Samples were collected from adults (>16 yrs) patients with CSF confirmed bacterial meningitis in the Netherlands between 2006 and 2015. Metadata includes patient outcome, species of bacteria, and for 467 samples a link to an ENA run with the associated bacterial genome (S. pneumoniae only).

  Study EGAS00001005993