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• Long-read trio sequencing of unsolved patients with intellectual disability

  Long-read sequencing (LRS) has the potential to comprehensively identify all medically-relevant genome variation, including variation commonly missed by short read sequencing (SRS) approaches. To determine this potential, we performed LRS up to 40x coverage using the Pacific Biosciences Sequel instrument for 5 patient-parent trios with intellectual disability, whose aetiology remained unresolved after SRS exomes and genomes. A first systematic assessment of LRS coverage showed that ~35Mb of the genome was only accessible by LRS and not SRS. Structural variant (SV) calling yielded on average 28,292 SV calls per individual, totalling 12.9 MB of sequence. Trio-based analyses showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, approximately 100,000 were located in the ~35Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known to cause Mendelian disorders. Although no clinical diagnoses were made in these 5 patients, our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.

  Study EGAS00001004319

• Liquid Biopsy Versus Tissue Biopsy to Assess Acquired Resistance and Tumor Heterogeneity in Gastrointestinal Cancers

  Tumor heterogeneity can drive the evolution of multiple tumor subclones harboring unique molecular resistance alterations in different metastatic lesions in an individual patient, under the selective pressure of therapy1-3. Studies have suggested that liquid biopsy may better capture the heterogeneity of acquired resistance, but systematic, direct comparisons of post-progression liquid vs. standard single-lesion tumor biopsies are lacking. In a prospective cohort of 44 patients with molecularly-defined gastrointestinal cancers and acquired resistance to targeted therapy, direct comparison of post-progression liquid vs. tumor biopsy revealed that liquid biopsy more frequently identified clinically-relevant resistance alterations and multiple resistance mechanisms, detecting resistance alterations not detected in matched tumor biopsy in 78% of cases. Whole-exome sequencing of serial cell-free DNA, tumor biopsies and rapid autopsy specimens elucidated geographic and evolutionary characteristics of heterogeneity. Our data suggest that acquired resistance is frequently characterized by profound tumor heterogeneity and highlight the potential clinical utility of liquid biopsy. Burrell, R. A. & Swanton, C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Molecular oncology 8, 1095-1111, doi:10.1016/j.molonc.2014.06.005 (2014). Misale, S. et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature 486, 532-536, doi:10.1038/nature11156 (2012). Ahronian, L. G. et al. Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations. Cancer Disco 5, 358-367, doi:10.1158/2159-8290.Cd-14-1518 (2015).

  Study phs001853

• Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy"

  Dataset of the study "Synergy study: "Tissue resident CD8+ T cell clonal expansion in advanced triple negative breast cancer is associated with response to chemoimmunotherapy". This dataset contains the cellranger's gene-expression matrices for the 5 prime single-cell RNA sequencing experiments

  Dataset EGAD50000000748

• Genomics of Blastic Plasmacytoid Dendritic Cell Neoplasm

  The goal of this study was to understand the genetic evolution and tumor phylogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN). BPDCN can present in patients with skin tumors of leukemia cells and no bone marrow or blood involvement, or alternatively, with both skin tumors and blood/bone marrow leukemia cells at the time of diagnosis. Here, we performed longitudinal sampling of tissues from patients with BPDCN, including both skin tumors and bone marrow, and in some cases serially at different time points through the course of diagnosis and treatment. These were studied by whole exome or whole genome DNA sequencing, comparing tumor samples to matched normal samples.

  Study phs003228

• STAMPEED: Myocardial Infarction Genetics Consortium (MIGen)

  Myocardial infarction (MI) is a common complex disease and the leading cause of death and disability worldwide. The genetic basis of this disease is largely unknown. It has been thought that early-onset MI events would have a substantially greater heritability, thus making DNA collections with younger individuals desirable. More recently, genome-wide association studies have become feasible through the development of whole genome arrays and a large catalogue of common variants reported in the International HapMap database. This study aims to use Affymetrix genotyping platform to do a whole genome scan in 3000 early-onset MI cases and 3000 matched controls from 6 study collection sites.

  Study phs000294

• HuBMAP: High Resolution 3D Mapping of Cellular Heterogeneity Within Multiple Types of Mineralized Tissues

  The overall goal of the study was to generate 3D single cell maps of healthy human knee cartilage. Articular cartilage from the weightbearing and non-weightbearing regions of the femoral condyles in healthy knees from young donors (n=12) was analyzed by bulk RNA-sequencing (RNA-Seq), single nuclei RNA (snRNA-seq) and ATAC-sequencing and by spatial transcriptomic methods (GeoMx, MERFISH and Xenium). These multimodal data and additional single cell RNA-sequencing (scRNA-seq) data were integrated to generate a comprehensive molecular, genomic and function annotation of chondrocyte populations. Regulatory mechanisms were derived by linking motifs in expressed genes, transcription factors and chromatin organization.

  Study phs003721

• Influence of age on molecular changes and treatment stratification in multimodal glioblastoma therapy

  Background: The increasing life expectancy has led to a rise in high-grade gliomas, particularly in patients of older age. The impact of chronological age, associated molecular changes and contributing factors on therapy response, progression-free survival (PFS) and overall survival (OS) remain uncertain. Methods: Between January 1st, 2016, and December 31th, 2021, patients with glioblastoma IDH-wt (CNS WHO grade 4) were included. RNA- and T-cell receptor sequencing was performed in a subset of patients. Primary outcome parameters were extent of resection (EOR), progression free- and overall survival. Multivariate analysis was performed to identify independent predictors of survival. Results: A total of 286 patients were included. The mean age was 66.4 years. Chronological age did not correlate with overall survival (r=0.12). With age, tumor immune composition changed towards macrophages with M2 phenotype and decreased numbers of CD8+ and neutrophiles. Aging related genes were not enriched. Beyond 69.5 years of age, despite similar PFS (p=0.0783), OS (p<0.0001) was significantly shorter, compared to younger patients. Extent of resection and adjuvant radiochemotherapy were significant predictors of OS (p<0.0001). No difference in PFS and OS was found between younger and older patients treated with maximal safe resection, followed by concomitant RT and chemotherapy and adjuvant chemotherapy. Conclusions: This study suggests that age alone should not be the sole determinant in therapeutic decision-making for glioblastoma patients. Gross total resection and adjuvant therapy, tailored to individual clinical status, significantly impact survival outcomes. Patient-specific treatment strategies are important to minimize undertreatment and optimize therapeutic outcomes in older patients.

  Study EGAS00001008246

• Investigation of human variation in healthy individuals on gene and protein levels

  The study examines human variation in healthy individuals, with samples taken from peripheral blood mononuclear cells. The study is a part of a larger effort to understand variants better both on level of genes and proteins. Thus for each DNA sample, corresponding protein samples are available.

  Study EGAS00001003590

• Treatment-mediated selection of lethal prostate cancer clones defined by copy number architectures

  Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient relationships of metastases that evade treatment, we performed genome- wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 142 metastatic regions from 10 organs harvested post-mortem from nine men who died from prostate cancer. We identified diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number change, we confirmed a common clone of origin across metastases and diagnostic biopsies; and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. Autosome-defined clusters were characterized by cluster-specific AR gene architectures that in two index cases were topologically more congruent than by chance (p-values 0.03, 3.07x10-8). Integration with anatomical site suggested patterns of spread and points of genomic divergence. Copy number boundaries identified treatment-selected clones with putatively distinct lethal trajectories.

  Study EGAS00001006598

• A somatic reference standard for cancer genome sequencing with COLO829

  Identification of somatic alterations in cancer has become feasible with the massive adoption of next generation sequencing. However, due to variability in sequencing and informatics pipelines, a common somatic reference is needed. We thus performed paired whole genome sequencing of a metastatic melanoma cell line (COLO829) and a matched lymphoblastoid line (COLO829BL) across three institutions (TGen, Illumina, Genome Sciences Centre at the British Columbia Cancer Agency). We performed a meta-analysis of all data, in combination with the originally reported analysis of these cell lines by Pleasance et al (PMID: 20016485), and report a somatic reference standard based on consensus events. DNA extractions, library preparation, sequencing, and analysis were separately performed at each site. Results were compiled with sequence data previously generated for the cell lines to identify true positive variants, collectively representing a somatic reference standard. Overall, common somatic events include point mutations, small insertion/deletions, and genes affected by concurrent copy number changes. We additionally show divergence of somatic mutations in COLO829 associated with differences in cell line lineage. We present this reference to the community as a standard for enabling interpretation and identification of somatic mutations across institutions and analytical pipelines.

  Study EGAS00001001385