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• The Role of Germline Mutation and Parental Age in Autism Spectrum Disorders

  <p>We will apply whole genome sequencing of trio families to determine how patterns of germline mutation throughout the genome determine risk for Autism Spectrum Disorder (ASD). We will investigate the nature intrinsic hypermutability and the extrinsic forces, such as paternal age, that influence rates of germline mutation. We will accomplish these goals through the following specific aims: Specific Aim 1 will characterize germline de novo mutations (DNMs) by whole genome sequencing in families. These studies will identify and validate ~8,000 de novo point mutations and structural variants in trios and controls to determine the parent of origin of DNMs. Specific Aim 2 will identify hot spots for germline mutation based on the regional density of DNMs in the genome, and determine the effects of DNA sequence features on rates of mutation. We will determine the association of mutation hotspots with ASD in the discovery sample and in genomic datasets from an independent sample of 2700 cases and 2700 controls. Specific Aim 3 will characterize the effects of extrinsic factors, including parental age and environment, on genome-wide rates of mutation. We will quantify the effect of paternal age on pathogenic and neutral alleles in sperm and investigate whether some DNMs confer a germline selective advantage. The findings of this study will provide fundamental insights into the genetic basis of autism risk and the genetic mechanism of the observed parental age effects in ASD. We will identify genes that confer significant risk for autism, and we will determine how intrinsic properties of the genome interact with extrinsic forces to determining risk for disease in offspring.

  Study phs001164

• The Human Pancreas Analysis Program (HPAP)

  The past decade has seen a dramatic improvement in our ability to phenotype and molecularly profile human tissues with unprecedented resolution at the genomic, epigenomic, protein, and functional levels. The Human Pancreas Analysis Program (HPAP), part of the Human Islet Research Network and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) through multiple NIH grants, is performing deep phenotyping of the human endocrine pancreas to better understand the cellular and molecular events that precede and lead to beta-cell loss and/or dysfunction in type 1 diabetes (T1D) and type 2 diabetes (T2D) as well as to accumulate, analyze, and distribute high-value data sets to the diabetes research community through the HPAP PANC-DB database (and additional details provided at that site). To this end, HPAP employs state-of-the-art technologies to perform comprehensive analyses of pancreas biology as it pertains to organ donors with T1D, autoantibody-positive donors without diabetes, donors with T2D, and control donors. Pancreas procurement and analyses take advantage of the expertise and extensive network of Organ Procurement Organizations (OPOs) and autoantibody screening centers established through the JDRF/The Lenona M. and Harry B. Helmsley Charitable Trust (HCT) – funded nPOD program. In contrast to nPOD, the major product provided by HPAP is not archived biomaterial subject to broad distribution, but rather, the delivery of extensive and high-quality molecular data sets to the diabetes research community in order to facilitate further discovery. Together, nPOD and HPAP are complementary programs that assist the diabetes community and afford the maximal opportunity for advancing knowledge about the pathogenesis of T1D and T2D.

  Study phs002465

• Genomic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia

  Pediatric leukemia is the most common type of childhood cancer and, despite tremendous progress in treatment, remains the second leading cause of cancer deaths in children. B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of pediatric leukemia. Recent studies using transcriptional profiling of large cohorts of pediatric B-ALL have shown that patients can be grouped into transcriptional subtypes that are often defined by specific driver mutations. Interestingly, many of these mutational subtypes are defined by gene fusions or rearrangements that drive altered expression of transcription factors (ETV6-RUNX1, PAX5, DUX4, TCF3-PBX1, ZNF384) or in chromatin regulatory machinery (KMT2A), suggesting that transcriptional dysregulation is a major driver of B-ALL. While the transcriptional distinctions are clear, the relationship between patients in terms of their chromatin regulatory landscape remains unclear. To address this, we profiled gene expression, open chromatin, and 3D genome folding in patient derived B-ALL samples. We identified that at the level of 3D genome organization, many chromatin interactions and looping events are shared across mutational subtypes, suggesting that shared transcriptional programs, in addition to group specific driver mutations, possibly regulate the chromatin landscape in B-ALL. Using RNA-seq and ATAC-seq data, we were able to identify "latent" signatures of expression related to non-mutant transcription factors (TFs) that also contribute to expression heterogeneity across TF subtypes. These are related to patient specific patterns of 3D genome folding, and in some cases, are predictive of disease outcomes. This study helps shed light on the chromatin landscape in B-ALL and furthers our understanding of the interactions between diverse mutant TFs that drive B-ALL and non-mutant TFs that help shape the B-ALL chromatin landscape.

  Study phs003226

• Impact of Genetic Variation on Response to GO Therapy in COG-AML Trials AAML03P1 and AAML0531

  The 340 de novo Acute Myeloid Leukemia (AML) patients (ages 1 month to 21 years) were enrolled in COG-AAML03P1 (NCT00070174). Everyone received standard chemotherapy regimen of ara-C, daunorubicin and etoposide (ADE) with addition of one 3 mg/m2 dose of Gemtuzumab Ozogamicin (GO) in induction 1 as well as in intensification II phase. The 1022 de novo AML patients (ages 0–30 years) were enrolled in COG-AAML0531 (NCT01407757). They were randomly assigned to receive either the standard ADE regimen (ADE arm, n = 511) or with the addition of one 3 mg/m2 dose of GO, during induction I as well as intensification II phase (ADE+GO arm, n = 511). Detailed study design, treatment regimen, and clinical outcomes of these two trials have been previously published (Cooper TM, Franklin J, Gerbing RB, et al., PMID:21766293 and Gamis AS, Alonzo TA, Meshinchi S, et al., PMID:25092781). The current study used genomic DNA from 1,225 pediatric patients treated in these two trials with 470 patients treated with standard chemotherapy in COG-AAML0531 (ADE arm) and 755 patients treated with addition of GO to standard therapy in COG-AAML03P1 and COG-AAML0531 trials (ADE+GO arm). The 132 SNPs in 42 genes within DNA-damage repair (DDR) pathways or genes implicated in mediating calicheamicin were selected for genotyping. These SNPs were genotyped using the Sequenom platform at the Biomedical Genomics Center, University of Minnesota. All SNPs had a call rate of more than 0.98 and were in accordance with the Hardy–Weinberg equilibrium. These genotypes were used to test for association with clinical endpoints as defined in the COG-AAML03P1 and COG-AAML0531 trials.

  Study phs003490

• CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory

  Foxp3-expressing CD25+CD4+ regulatory T cells (Tregs) are abundantly infiltrating into tumor tissues, hindering effective anti-tumor immunity. Here, assuming that such tumor Tregs were clonally expanding by recognizing tumor-associated antigens, we attempted to characterize them by their gene expression profiling and T-cell receptor (TCR) clonotyping at the single-cell level. We found that they predominantly expressed the chemokine receptor CCR8: ~40% of tumor Tregs, less than 10% of Tregs in other tissues, and few tumor-infiltrating conventional T cells expressed CCR8 in mice and humans. CCR8+ tumor Tregs were phenotypically highly differentiated and functionally stable. One injection of anti-CCR8 mAb with high antibody-dependent cellular cytotoxic activity was indeed able to specifically deplete clonally expanded tumor Tregs and thereby eradicate established tumors in mice. The depletion predominantly expanded tumor-infiltrating CD8+ effector T cells, which were different in activated or exhausted patterns from those seen after immune checkpoint blockade by anti-PD-1 mAb. The treatment also evoked potent secondary immune responses against the same tumor cell line inoculated several months after tumor eradication, indicating that the anti-CCR8-induced memory-type tumor-reactive effector T cells were, once induced, resistant to recovered Treg suppression. In contrast to such evocation of potent tumor immunity, anti-CCR8 treatment scarcely elicited discernable autoimmunity in mice, contrasting with a similar treatment for systemic whole Treg depletion, which induced histologically and serologically evident autoimmunity. Thus, temporary and specific depletion of clonally expanded Tregs in tumor tissues by cell-depleting anti-CCR8 mAb is sufficient to evoke potent tumor immunity with long-lasting memory and without serious autoimmunity.

  Study JGAS000312

• Genomic platform specific polygenic risk scores impact breast cancer risk stratification

  Background: At present, there is no consensus on which genotyping platform should serve as the standard for clinical polygenic risk score (PRS) implementation. Previous studies have compared the overall performance and concordance of different genotyping and sequencing technologies; however, these analyses have generally averaged the results over the whole genome. We evaluated differences in a 313-variant breast cancer PRS (PRS313) across genomic platforms and their impact on risk stratification. Methods: We compare PRS313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes are designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing profiles indels. Concordance of high-risk classification (PRS313scoresum > 0.6) across platforms is assessed using Kappa statistics. Results: In saliva samples, indel concordance with Sanger sequencing varies widely (Kappa: 0.007-1.000). PRS313-ThermoFisher is predictable from other platforms using linear models, despite systematic differences. Greater agreement is observed between arrays with high imputation overlap (e.g., GDA ~ GSA slope=0.986). Agreement in high-risk classification before mean correction is moderate (Fleiss's Kappa=0.552) and improves after mean correction (Kappa=0.650). Arrays with similar designs show higher agreement before mean correction (Kappa=0.745). Mean correction narrows high-risk proportions from 4-45% to 15-21%. Overall, 26 of 92 samples are classified as high risk on at least one platform, but only 7 are high risk across all. When restricting to identical variants across all platforms for PRS313 calculation, the corresponding number of high-risk individuals are 24 and 11. Conclusion: Our findings demonstrate that platform-specific variability can influence PRS313 estimates to potentially reclassify individuals around clinically relevant thresholds.

  Study EGAS00001008439

• An integrative model of pathway convergence in genetically heterogeneous blast crisis chronic myeloid leukemia (CML)

  Targeted therapies against the BCR-ABL1 kinase have revolutionized treatment of chronic phase (CP) chronic myeloid leukemia (CML). In contrast, management of blast crisis (BC) CML remains challenging because BC cells acquire complex molecular alterations that confer stemness features to progenitor populations and resistance to BCR-ABL1 tyrosine kinase inhibitors. Comprehensive models of BC transformation have proved elusive because of the rarity and genetic heterogeneity of BC, but are important for developing biomarkers predicting BC progression and effective therapies. To better understand BC, we performed an integrated multiomics analysis of 74 CP and BC samples using whole-genome and exome sequencing, transcriptome and methylome profiling, and chromatin immunoprecipitation followed by high-throughput sequencing. Employing pathway-based analysis, we found the BC genome was significantly enriched for mutations affecting components of the polycomb repressive complex (PRC) pathway. While transcriptomically, BC progenitors were enriched and depleted for PRC1- and PRC2-related gene sets respectively. By integrating our data sets, we determined that BC progenitors undergo PRC-driven epigenetic reprogramming toward a convergent transcriptomic state. Specifically, PRC2 directs BC DNA hypermethylation, which in turn silences key genes involved in myeloid differentiation and tumor suppressor function via so-called epigenetic switching, whereas PRC1 represses an overlapping and distinct set of genes, including novel BC tumor suppressors. On the basis of these observations, we developed an integrated model of BC that facilitated the identification of combinatorial therapies capable of reversing BC reprogramming (decitabine+PRC1 inhibitors), novel PRC-silenced tumor suppressor genes (NR4A2), and gene expression signatures predictive of disease progression and drug resistance in CP.

  Study EGAS00001001751

• Comparison of capture-based method for transcriptome profiling of formalin-fixed paraffin embedded tumor samples

  Background: The need for fresh frozen (FF) tissue limits implementing RNA sequencing (RNA-seq) in the clinic. The majority of clinical samples are stored as formalin-fixed, paraffin-embedded (FFPE) tissues. Exome capture platforms have been developed for RNA-seq from FFPE samples. However, these methods have not been systematically compared. Methods: Transcriptomic analysis of 32 FFPE tumor samples from 11 patients was performed using three exome capture-based methods: Agilent SureSelect V6, TWIST NGS Exome, and IDT XGen Exome Research Panel. We compared these methods to TruSeq RNA-seq of fresh frozen (FF-TruSeq) tumor samples from the same patients. We assessed the recovery of clinically relevant biological features. Results: The Spearman's correlation coefficients between the global expression profiles of the three capture-based methods from FFPE and matched FF-TruSeq were high (rho = 0.72-0.9, p < 0.05). A significant correlation between the expression of key immune genes between individual capture-based methods and FF-TruSeq (rho = 0.76-0.88, p < 0.05) was observed. All exome capture-based methods reliably detected outlier expression of actionable genes, including ERBB2, MET, NTRK1, and PPARG. In urothelial cancer samples, the Agilent assay was associated with the highest molecular subtype concordance with FF-TruSeq (Cohen's k = 0.7, p < 0.01). Both Agilent and IDT detected all the clinically relevant fusions that were initially identified in FF-TruSeq. Conclusion: All exome capture-based methods had comparable performance and concordance with FF-TruSeq. By enabling the interrogation of FFPE tumor samples, our findings will enable the implementation of RNA-seq in the clinic to guide precision oncology approaches.

  Study EGAS00001005255

• Stromal-induced epithelial-mesenchymal transition induces drug resistance in acute lymphoblastic leukemia

  Bone marrow (BM) microenvironment-induced drug resistance in acute lymphoblastic leukemia (ALL) is thought to be mediated by intercellular interaction of leukemic cells with BM niches, but the mechanistic basis of resistance is poorly understood. Here, we genomic and functional analyses, we show that ALL-BM mesenchymal stromal cells (MSC) interactions encompass direct cell-cell adhesion via integrin α4β1, uni-directional secretion of soluble factors from MSC to ALL, and bidirectional transfer of cellular vesicles through tunneling nanotubes. We show that this crosstalk drives an epithelial-mesenchymal transition (EMT)-like program in ALL cells adhering to MSC, thereby triggering stem cell-like features including drug resistance and survival advantage. Moreover, single-cell RNA sequencing of cell line and primary ALL samples identified a hybrid cell state derived from B-ALL adhered to MSC, that exhibits both B-ALL and MSC gene signatures that are orchestrated by an EMT-like program. Multiple EMT-activating pathways including WNT/β-catenin, cytokine/STAT3, TGFβ, NOTCH1, and NF-κB-dependent signaling pathways are activated in MSC-adherent ALL cells; however, only the inhibition of either WNT/β-catenin or cytokine/STAT3 pathway could attenuate the survival and drug resistance of ALL cells adherent to MSC. Notably, we identified that this hybrid cell state exhibited elevated WNT/β-catenin-mediated transcriptional activity. Finally, we show that blocking of the interaction of β-catenin and CBP interaction abrogates the survival and drug resistance of ALL cells adhered to MSC, indicating that targeting of an EMT-like program is potential therapeutic regimen in targeting cell extrinsically acquired drug resistance in ALL.

  Study EGAS00001006120

• Cholesterol homeostasis and lipid raft dynamics at the basis of tumor-induced immune dysfunction in chronic lymphocytic leukemia

  Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. Consequently, CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.

  Study EGAS50000000933