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• Childhood Cancer Data Initiative (CCDI): Genomic Analysis in Pediatric Malignancies

  Pediatric solid tumors are highly heterogeneous, encompassing a large number of histotypes. The genomic landscape of these diseases is characterized by few single-nucleotide variants (SNVs) compared to adult cancers. In contrast, many exhibit a high prevalence of structural or epigenetic changes that alter gene expression, underlining the need for comprehensive genomic approaches such as whole-genome sequencing (WGS). Several studies have specifically addressed the clinical utility of genomic analysis in the pediatric and AYA cancer setting. Review of these studies point to key challenges that must be addressed in order to advance the routine use of genomics in this population. We have established a large collection of solid tumor tissue samples through our biobanking efforts. Where possible, we obtain longitudinal samples from the same patient. These primary patient samples and their corresponding germline have been analyzed using whole genome and whole transcriptome sequencing methods and have been linked to clinical metadata using both manual curation and robust methods for automatic extraction from the electronic health record (EHR). Importantly, research-grade genomic analysis is performed in parallel to our CLIA-grade sequencing (“UCSF500”) efforts for some of the patients in this study cohort and have been submitted as part of the American Association for Cancer Research's project GENIE and/or the National Childhood Cancer Registry. For our sequenced tumor samples, we have retrospective clinical data and ongoing efforts to prospectively record key events throughout the patient's cancer journey. In our solid tumor program, we have developed many patient-derived xenograft models and a number of PDX-derived cell lines. These unique models have been evaluated using genomic and functional approaches including (in some cases) treatment with conventional chemotherapy or investigational agents. Lastly, these samples were collected from a population that is among the most diverse in the nation and includes significant numbers of Asian, Latino, Indigenous and African-American patients, groups that are traditionally underrepresented in many banking efforts.

  Study phs002430

• The Effects of Long-Term Heavy Metal Exposure on Transcriptome Landscape in Human Peripheral Blood Cells

  The present study investigates the impact of long-term residence in a mining area on transcriptome changes induced by heavy metal exposure in human peripheral blood mononuclear cells (PBMCs) from 65 healthy subjects selected from the general population. This study includes the same participants which were recruited in our previous investigation on heavy metal long-term environmental exposure-related gene-specific methylation changes (phs003392.v1.p1). We performed a differential expression analysis to compare the mRNA transcriptome of 31 residents from the mining region (MRR) - individuals living in the Kapan mining area with reported environmental exposures to heavy metals - with that of 34 residents from non-mining regions (NMR) - individuals residing at a considerable distance from mining locations. We also evaluated the potential association of gene expression profiles with the blood metallome, including levels of Ca, Mg, Co, Fe, Mn, Cu, Mo, Se, Zn, As, Sb, Tl, Be, V, Ni. Poly-A selected strand-specific mRNA library was prepared with Illumina Stranded mRNA Prep kit. The sequencing was performed on the Illumina NovaSeq-6000 platform with 38.5 million single-end 100 bp reads on average generated per sample. Quality checking of the sequencing data was performed using Illumina Basespace reports and the program FastQC (V0.10.1). Reads were aligned against the Human Genome Hg38 using STAR (version 2.7.1a). According to our findings, long-term residence in a mining area is correlated with alterations in the blood transcriptome, with responses varying by sex. Pathway analysis revealed upregulation of immune response related pathways, and downregulation of translation and ribosome biogenesis in the PBMCs of the MRR. Pathways related to metal ion transmembrane transport, epigenetic modifications (histone deacetylases (HDACs) and DNA methylation) were upregulated in males, while in females mostly transcripts involved in inflammation and cytokine mediated signaling were upregulated. Additionally, among the dysregulated pathways, the TNF-α signaling via NF-κB showed opposite changes in females and males.

  Study phs003657

• Diagnostic utility of clinical genome reanalysis in rare pediatric disorders using long-read sequencing

  More than half of presumed genetic disease cases remain undiagnosed following exome and/or short-read genome sequencing (SR-GS). Long-read genome sequencing (LR-GS) has emerged as a promising next step for uncovering etiologies missed by current standard-of-care SR genetic testing. However, structural variant (SV) interpretation remains a major challenge in LR-GS clinical pipelines, owing to limitations in SV call reliability, population allele frequency estimation, and evaluation of functional impact. To further develop strategies for the effective clinical use of LR-GS, we performed LR-GS using PacBio HiFi technology on 20 families with developmental disorders of suspected genetic origin and prior negative or inconclusive genetic testing (including exome and/or genome sequencing). Analysis was performed using a comprehensive pipeline integrating phased assembly– and read-based variant calling with LR-GS population allele frequency filtering. Phenotype-driven variant prioritization using Human Phenotype Ontology (HPO) terms was performed using a combination of tertiary analysis solutions, including publicly (SvAnna) and commercially (Illumina Emedgene) available tools. Definitive diagnostic findings were identified in 1/20 (5%) families. Variants of suspicious diagnostic significance were identified in 6/20 (30%). All findings of diagnostic significance were clinically confirmed using the proband’s prior clinical SR sequencing results, demonstrating the value of reanalysis and highlighting differences in clinical interpretation. One case harbored a homozygous ~50 kb deletion of initial interest that was only detected with LR-GS; however, it was ruled inconclusive based on frequency data from LR-GS population databases, underscoring the necessity of population filtering for structural variant clinical interpretation. Collectively, the observed increase in diagnostic yield (by 35% including suspicious findings) in this exome-/SR-GS-negative clinical cohort was driven primarily by genome reanalysis rather than identification of variants unique to LR-GS data. Additional functional studies are necessary to elucidate the clinical relevance of suspicious findings.

  Study EGAS50000001464

• UK10K COHORT ALSPAC

  The UK10K project proposes a series of complementary genetic approaches to find new low-frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome-wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein-coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will directly analyse quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. The Avon Longitudinal Study of Parents and Children (ALSPAC) is a two-generation prospective study. Pregnant women living in one of three health districts in the former county of Avon with an expected delivery date between April 1991 and December 1992 were eligible to be enrolled in the study, and this formed the initial point of contact for the development of a large, family based resource. Information has been collected on the children and the mothers through retrieval of biological materials (e.g. antenatal blood samples, placentas), biological sampling (e.g. collection of cord blood, umbilical cord, milk teeth, hair, toenails, blood and urine), self-administered questionnaires, data extraction from medical notes, linkage to routine information systems and at repeat research clinics.

  Study EGAS00001000090

• GDAP___Genome_Diversity_in_Africa_Project

  The Genomic Diversity in Africa Project (GDAP) started with the plan to develop a genomic resource from African populations, characterise genomic diversity and population history, and facilitate clinical studies in Africa. Currently, 25 individuals from 24 ethnolinguistic groups have been whole-genome sequenced at high depth totalling 585 individuals. An additional 41 individuals have been sequenced with 10X Genomics libraries. At this stage, the initial curation of this dataset has been finished and we are performing the analysis in coordination with our collaborators. The current state of the GDAP represents a very diverse panel of African populations that maximizes geographical and ethnic variation and represents a great starting point to achieve the aforementioned goals. However, southern sub-Saharan countries, Bantu speakers and hunter gatherer groups are currently underrepresented, despite being crucial to understand the evolutionary history of the continent. After extensive effort to collate studies documentation, we finally have the opportunity to sequence 600 new individuals from these groups, including countries as Gabon, Rwanda and Zambia, and address these deficiencies. We aim to proceed with the same strategy: to sequence at high depth 25 individuals with standard PCR free libraries, with 2 additional individuals with 10X Genomics Chromium libraries per ethnolinguistic group. The former allows a good representation of variants down to low frequency in any given population, and the latter allows accurate phasing and the analysis of structural variation. By including these new populations, we want to investigate three crucial questions in African history in addition to the initial objectives: the Bantu expansion, the evolutionary history of hunter gatherers and the transatlantic slave trade. Additionally, the expanded dataset will help us better discover the genetic variation present in Africa and characterize the African pangenome. 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 EGAS00001003602

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006103

• The University of Hong Kong Colon Cancer GCV Study

  Background: Ganciclovir (GCV) is widely used in solid organ and hematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig¬¬ were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV¬sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

  Study EGAS00001006707

• High-throughput telomere length measurement at nucleotide resolution using the PacBio high fidelity sequencing platform, P49-P104 and run1 replicates

  Telomeres are specialized nucleoprotein structures at the ends of linear chromosomes that are essential for the stability as well as the complete replication of the human genome. The progressive shortening of steady-state telomere length in normal human somatic cells is a promising biomarker for age-associated diseases. However, there remain substantial challenges in quantifying telomere length in clinics and research laboratories due to the lack of accurate and high-throughput telomere length measurement method. Here, we describe a novel workflow to capture and analyze telomeres accurately at the single-nucleotide resolution. By using newly designed telobaits that are complementary to the single-stranded G-rich 3’ telomeric overhangs, we can specifically and efficiently capture full-length telomeres and subject them to single-molecule real-time (SMRT) sequencing. We show that the telomere length can be measured at nucleotide resolution using the PacBio high fidelity (HiFi) sequencing platform, which provides the necessary accuracy and throughput to uncover the steady-state telomere length distribution in human culture cell lines as well as clinical patient samples. This new method is a valuable tool not only in population-wide epidemiology studies but also for the longitudinal assessment of telomere attrition in individuals. Our results also reveal the extreme heterogeneity of telomeric variant sequences (TVSs) that is dispersed throughout the telomere repeat region. Importantly, the unique distribution pattern and sequence of TVSs in individuals may be used as a fingerprint for sample identification. In addition, the presence of TVSs disrupts the continuity of the canonical (5’-TTAGGG-3’)n telomere repeats, which could affect the binding of shelterin complexes at the chromosomal ends. Therefore, TVSs may act as a form of genetic polymorphisms that impairs telomere protection. Together with the absolute telomere length in each individual, TVSs may have profound implications in human aging and diseases.

  Study EGAS00001006595

• Proteomic Analysis of Non-Muscle Invasive and Muscle Invasive Bladder Cancer Highlights Distinct Subgroups With Metabolic, Matrisomal, and Immune Hallmarks

  We present the proteome biology of bladder cancer based on a cohort comprising treatment-naïve non-muscle invasive (NMIBC, N=17) and treatment-naïve muscle-invasive bladder cancer (MIBC, N=51), as well as neoadjuvant-treated MIBC (N=11); using formalin-fixed, paraffin-embedded samples and data-independent acquisition yielding >8,000 protein identifications. The NMIBC proteome reveals two subgroups that represent cell adhesion or lipid metabolism biology. MIBC, compared to NMIBC, shows an altered metabolic proteome together with enrichment of extracellular matrix (ECM), immune response, and complement proteins; in line with three proteomic MIBC subgroups that represent ECM, metabolic, or immune signatures. The ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells, while markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T-cells are a hallmark of the immune subgroup. Infiltration of CD8+ PD1+ positive cytotoxic T cells correlated with PD-L1 expression of MIBC, as demonstrated by multiplex immunofluorescence analysis. The metabolic subgroup presents a comparably immune-depleted microenvironment. YAP1 signaling is particularly prominent in the ECM subgroup. The protein BSCL2 emerges as a prognostic marker for MIBC. We highlight increased endogenous proteolysis in MIBC alongside the upregulation of matrix metalloproteases exceeding the upregulation of their endogenous inhibitors. Genomic panel sequencing underlines prevalent FGFR3 mutations in NMIBC and prevalent TP53 mutations in MIBC, but a genomic underpinning of the MIBC subgroups remains elusive. Proteogenomic analysis yields protein-level evidence for more than 1,300 single amino acid variants. The proteomes of neoadjuvant-treated MIBC resembled treatment-naïve MIBC. Tumor-stroma interaction of MIBC was further investigated by proteomic analysis of patient-derived xenografts of MIBC. Our study adds to the proteome-level understanding of bladder cancer.

  Study EGAS00001007290

• Microvascular Permeability, Inflammation, and Lesion Physiology in Endometriosis: A Microphysiological Systems Approach

  The goal of the study is to identify novel molecular pathways involved in the etiology of endometriosis and to develop in vitro model systems to enable the study of the mechanisms regulating reproductive function. Using a physiomimetic modeling approach, primary tissue samples of the human endometrium derived from patients diagnosed with and without endometriosis and/or endometriotic diseases (e.g. adenomyosis) were used for secondary analysis using multi-omic systems biology analysis and to build tissue engineered models. We performed single cell RNA sequencing (scRNA-Seq, N=6)) to study the cellular and transcriptomic composition of the endometrial tissue microenvironment and proteomics (LC-MS/MS) to study protein-level signaling pathways and the matrisome of the native endometrium. Systems biology analysis of these datasets helped identified a putative dysregulated inflammatory signaling pathway in endometriosis patients compared to controls. Moreover, subsets from these scRNA-Seq and proteomic datasets were used to aid the design of a synthetic extracellular matrix hydrogel as an in vitro platform for the culture of endometrial cells. Tissue-engineered synthetic PEG hydrogel enables the simultaneous co-culture of endometrial epithelial organoids and stromal fibroblasts in a fully defined, 3D, and tunable environment. We demonstrated that the in vitro co-culture model recapitulates key phenotypic processes observed across the human menstrual cycle in response to sex hormone stimulation through both biochemical and transcriptomic (bulk RNA-sequencing) analysis. This model will enable future mechanistic studies that examine origins of endometriotic disease phenotypes. The transcriptomic data generated for this study including the scRNA-Seq data from primary human endometrial tissues and the bulk RNA-Seq datasets from the experimental co-culture models is available through dbGAP.

  Study phs003326