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• Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities DNA-Methylation

  Atypical teratoid/rhabdoid tumors (ATRTs) represent a rare, but aggressive pediatric brain tumor entity. They are genetically uniquely defined by alterations in the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. ATRTs can be further classified in different molecular subgroups based on their epigenetic profiles. Although recent studies suggest that the different subgroups have distinct clinical features, subgroup-specific treatment regimens have not been developed thus far. This is hampered by the lack of pre-clinical in vitro models representative of the different molecular subgroups. Here, we describe the establishment of ATRT tumoroid models from the ATRT-MYC and ATRT-SHH subgroups. We demonstrate that ATRT tumoroids retain subgroup-specific epigenetic and gene expression profiles. High throughput drug screens on our ATRT tumoroids revealed distinct drug sensitivities between and within ATRT-MYC and ATRT-SHH subgroups. Whereas ATRT-MYC universally displayed high sensitivity to multi-targeted tyrosine kinase inhibitors, ATRT-SHH showed a more heterogeneous response with a subset showing high sensitivity to Notch inhibitors, which corresponded to high expression of Notch receptors. Our ATRT tumoroids represent the first pediatric brain tumor organoid model, providing a representative pre-clinical model which enables the development of subgroup-specific therapies.

  Study EGAS00001006881

• MRCA and MRCE SNP genotypes

  Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression based on approximately 400K SNPs and 50K transcripts in 400 sib pairs from the MRCA family panel has been widely used to interpret the results of GWAS. Here, we more than double the size of our initial dataset with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole genome expression array. We have used new statistical methods for dimension reduction to account for non-genetic effects in estimates of expression levels and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false discovery rates and increased the number of eQTLs mapped either locally or at a distance (i.e. in cis or trans) from 1,534 in the MRCA dataset to 4,452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7,302. Using the same methods and imputed SNPs in the newly acquired MRCE dataset we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database (http://www.hsph.harvard.edu/faculty/liming-liang/software/eqtl/) based on these results is freely available to help define the function of disease-associated variants.

  Study EGAS00000000137

• Circulating tumor cells Exome sequencing from breast cancer

  Single cell technologies allow interrogating the extent of tumor heterogeneity, providing novel insights into tumor evolution and treatment resistance mechanisms. Here, we investigated the level of genetic heterogeneity among circulating tumor cells (CTCs) at the single nucleotide variation and copy number aberration (CNA) levels and compared it to synchronous matched primary tumor/metastatic lesion from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive (HER2+) and estrogen-receptor-positive (ER+) tumors. Whole exome sequencing was performed on 3 synchronous bulk tumor tissue and 21 single/pooled CTC samples. When comparing bulk tissue with CTCs from the same patient, we found similar CNA profiles and the same patient-specific driver mutations for the HER2+ and TNBC tumors. Different CNA profiles and driver mutations were found for the ER+ tumor, with two distinct clones being identified in the CTCs, one harboring an activating ESR1 mutation, the other one bearing a TP53 mutation. These data suggest that tumor tissue and CTCs provide in a subset of patients complementary clinically relevant information to map tumor heterogeneity and monitor tumor evolution. Further validation is needed.

  Study EGAS00001005228

• Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY)

  The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) has sponsored a consortium of investigators to conduct a clinical treatment trial, Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY). The primary objective of the TODAY trial is to compare the efficacy of three treatment arms on time to treatment failure based on glycemic control. The secondary aims are to:compare and evaluate the safety of the three treatment arms;compare the effects of the three treatments on the pathophysiology of type 2 diabetes (T2D) with regards to beta cell function and insulin resistance, body composition, nutrition, physical activity and aerobic fitness, cardiovascular risk factors, microvascular complications, quality of life, and psychological outcomes;evaluate the influence of individual and family behaviors on treatment response; andcompare the relative cost effectiveness of the three treatment arms.The three treatment regimens are: (1) metformin alone, (2) metformin plus rosiglitazone, and (3) metformin plus an intensive lifestyle intervention called the TODAY Lifestyle Program (TLP). The study recruits patients over a three-year period and follows patients for a minimum of two years. Patients are randomized within two years of the diagnosis of T2D.

  Study phs002447

• Amplicon sequencing data from organoids of colorectal cancer patients.

  The dataset includes 13 bam files. Each bam file is a different colorectal cancer patient organoid.

  Dataset EGAD00001004313

• RBWES

  Retinoblastoma is a rare childhood cancer of the retina. We studied retinoblastoma by Whole-Exome-Sequencing.

  Dataset EGAD00001007591

• GMKF: Kids First Pediatric Research Program on Congenital Cranial Dysinnervation Disorders and Related Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Gabriella Miller Kids First Pediatric Research Program) (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both, childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. Whole Genome Sequence (WGS) and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. Goals of this ongoing study are to identify novel "congenital cranial dysinnervation disorder" (CCDD) genes and define the role of the wildtype and mutant genes in normal and aberrant development. The umbrella term (CCDD) refers to congenital birth defects with malformation of one or more cranial nerves, typically resulting in limitations of eye and/or face movement. Examples of CCDDs include congenital fibrosis of the extraocular muscles (CFEOM), congenital ptosis, Duane retraction syndrome (DRS), horizontal gaze palsy with progressive scoliosis (HGPPS), congenital 3rd, 4th or 6th nerve palsies, Moebius syndrome (MBS), and hereditary congenital facial paresis (HCFP). In some cases, anosmia, and disorders of hearing, sucking, chewing, swallowing, and breathing may also be classified as CCDDs. CCDDs can be accompanied by additional birth defects such as intellectual and social disabilities, developmental delays, limb anomalies, and cardiac, GI, and GU disorders. The genetic basis of multiple CCDDs has been determined, and the gene mutations typically alter cranial motor neuron identity or function, or perturb axon growth and guidance. Despite these successes, the genetic etiologies of many inherited CCDDs remain unidentified.

  Study phs001247

• EORTC-26101 sequencing data

  The dataset contains panel sequencing data of 170 genes from 380 patients of the EORTC-26101 trial. The corresponding methylation data is available via the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) repository with the accession number GSE237103.

  Dataset EGAD00001011160

• scRNA-seq of a 3D human cortical tissue model from human iPSCs exploring WT versus APP KI genotypes as well as Abeta/Aducanumab treatments

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model across cell lines, distinct genotypes (WT and APP KI) and in presence of Abeta/Aducanumab treatments. Samples include distinct conditions as described in the Study section. The dataset was generated using the BD Rhapsody technology and sequenced paired-end with Illumina NovaSeqX. Information on the multiplexing of samples is reported in the Analyses section.

  Study EGAS50000001397

• An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons

  Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using a GLP approved HTT assay. HD patients’ fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10nm without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Amongst, a 115bp frameshift-inducing exon in the HTT transcript in Branaplam treated cells from Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients’ fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.

  Study EGAS00001006289