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• Biopsy-Derived Organoids in Personalised Early Breast Cancer Care: Challenges of Tumour Purity and Normal Cell Overgrowth Cap Their Practical Utility

  The ability to establish organoids composed exclusively of tumour rather than healthy cells is essential for their implementation into clinical practice. Organoids have in recent years emerged as a powerful tool to expand patient material in culture and generate modifiable 3D models derived from humans or animal models. For translational research, they enable the creation of model systems for an ever-increasing number of cell types and diseases. And in personalised medicine, they potentially allow for functional drug testing with high predictive power in certain settings. We found that using biopsy material from untreated, early-stage primary breast cancer patients poses significant challenges for consistently culturing tumour cells as organoids. Specifically, we observed frequent outgrowth of genetically normal, non-cancerous epithelial cells. We analysed >100 biopsy samples from early-stage breast cancer and present our large collection of >70 organoid lines. We also show methods of assessing successful tumour cell culture in a time and cost-efficient manner, proving a high rate (>85%) of normal cell overgrowth in early-stage breast cancer organoids. Finally, we show a number of successful attempts to culture cancer organoids from mastectomy-derived tissue of advanced, metastatic breast cancer. We conclude that the usefulness of organoids from early breast cancer for translational research and personalised medicine, especially guidance of adjuvant or post-surgical maintenance therapy, is strongly limited by the low success rate of culturing cancerous cells under organoid conditions.

  Study EGAS50000000605

• Molecular Characterization of Clinical Renal Tumors

  We performed comprehensive molecular profiling of renal tumors, including whole exome sequencing and transcriptome sequencing, derived from patient samples. This project additionally explores mechanisms of response and resistance to existing and emerging therapies in this disease, as well as mechanisms of tumor evolution in the context of treatment.

  Study phs001018

• Mid-frequency hearing loss is a characteristic clinical feature of OTOA-associated hearing loss

  In this study, we performed NGS analysis of a large Japanese hearing loss cohort, and identified 7 patients with OTOA-associated hearing loss. As novel clinical features identified in this study, the audiometric configurations of OTOA-associated hearing loss patients was found to be mid-frequency.

  Study JGAS000200

• Spatial and temporal transcriptome analysis on human skeletal muscle regeneration

  Skeletal muscle carries a unique ability for adaptation as well as regeneration that highly depends on a supportive cellular microenvironment. Here we show that spatial and single-cell transcriptomic analysis in human skeletal muscle is a unique approach to illuminate cellular interactions in the microenvironment.

  Study EGAS50000000182

• Long-read whole genome sequencing as a tool for variant detection in inherited retinal dystrophies

  Advances in whole-genome sequencing (WGS) have significantly enhanced our ability to detect genomic variants underlying inherited diseases. In this study, we performed long-read WGS on 24 patients with inherited retinal dystrophies (IRDs) to validate the utility of nanopore sequencing in detecting genomic variations. We confirmed the presence of all previously detected variants and demonstrated that this approach allows for precise refinement of structural variants (SVs). Furthermore, we could perform genotype phasing by sequencing only the probands, confirming variants were inherited in trans. Moreover, nanopore sequencing enabled the detection of complex variants, such as transposon insertions and structural rearrangements. This comprehensive assessment illustrates the power of long-read sequencing in capturing diverse forms of genomic variation and in improving diagnostic accuracy in IRDs.

  Dataset EGAD50000001238

• The effect of freezing delay of cell-type specific transcriptome responses in human brain via snRNA-seq

  In other analysis in the current manuscript, we find a similar gene signature (to dissociation based artifacts in mouse and human tissue) is present in post-mortem microglia and astrocytes, across all snRNA-seq datasets analyzed, although it is highly variable between subjects. ​ Using acutely-resected neurosurgical tissue, we performed single-nucleus RNA-seq and reveal that a similar signature can be detected in microglia following prolonged exposure to room temperature. Tissue handling and methods details, as well as sequencing and analysis details) can be found in the methods section of related manuscript (Marsh et al., 2022). Together, these results suggest that the presence of this signature in post-mortem brain samples may be the result of a combination of acute pre-mortem (agonal state, cause of death, comorbidities, etc.) and post-mortem (post-mortem interval (PMI), storage time, RNA quality, etc.) variables and may not represent normally present cell state.

  Dataset EGAD00001008541

• Human and rat skeletal muscle multi-omic profiling

  Skeletal muscle accounts for the largest proportion of human body mass, on average, and is a key tissue in complex diseases and mobility. It is composed of several different cell and muscle fiber types. Here, we optimize single-nucleus ATAC-seq (snATAC-seq) to map skeletal muscle cell-specific chromatin accessibility landscapes in frozen human and rat samples, and single-nucleus RNA-seq (snRNA-seq) to map cell-specific transcriptomes in human. We additionally perform multi-omics profiling (gene expression and chromatin accessibility) on human and rat muscle samples.

  Study EGAS00001005730

• Exome sequencing of advanced hepatocellular carcinoma

  The aim of our project is to decipher the genomic of advanced hepatocellular carcinoma using whole exome sequencing. To this purpose, we aim to compare genetic landscape of advanced hepatocellular carcinoma with early tumor in order to understand the mechanisms of tumor progression. This work will also help to identify new therapeutic targets potentially useful to treat patients at advanced stage. This dataset contain whole exome sequencing aligned reads for 41 tumor with matched normal samples

  Dataset EGAD00001004555

• Genome-Wide Association Study of Anorexia Nervosa (Price Foundation, Klarman Family Foundation, Center for Applied Genomics at the Children's Hospital of Philadelphia, Scripps Translational Sciences Institute Clinical Translational Science Award)

  Twin studies are consistent with substantial heritability in anorexia nervosa (AN), although detecting and confirming individual risk alleles has been difficult, due to small effects of single alleles and limited samples in prior studies. Methods: 1105 AN DNA samples obtained in a multisite study and 3733 pediatric patients of normal body weight were genotyped using the Illumina 610Q chip at The Center for Applied Genomics at The Children's Hospital of Philadelphia. Cases and controls were of European ancestry. Single nucleotide polymorphism (SNP) genotypes were subjected to quality control procedures, including elimination of SNPs with: call rates < 95%, minor allele frequency < 5%, and if Hardy-Weinberg equilibrium testing yielded p < 0.0001. Samples were removed if not of European ancestry or if showing cryptic relatedness. Eight AN DNA samples were deleted for low call rate, and 51 AN samples were deleted for cryptic relatedness. The statistical program, PLINK, was used to calculate a P value for each SNP passing quality control using the Cochran-Armitage trend test. The PennCNV program was used to define copy number variation (CNV). Results: We performed a genome-wide association study (GWAS) using with 1033 AN cases and 3733 controls (genomic inflation factor = 1.08). There were 11 SNPs with P<1X10-5 [(rsID, chromosome location, nearest gene, distance to nearest gene (base-pair), P value) rs6959888, 7q21.13, ZNF804B, 0, 1.63E-06; rs17725255, 20p11.23, CSRP2BP, 39396, 1.72E-06; rs10494067, 1p13.3, NTNG1, 0, 5.83E-06; rs2383378, 14q12, AKAP6, 0, 6.41E-06; rs410644, 5q14.1, SSBP2, 40462, 6.74E-06; rs4479806, 5p14.1, CDH9, 156926, 7.79E-06; rs957788, 13q33.3, FAM155A, 0, 8.11E-06; rs830998, 2q31.1, LRP2, 0, 8.68E-06; rs6782029, 3p25.3, VGLL4, 0, 9.04E-06; rs512089, 9p21.3, ELAVL2, 47984, 9.85E-06; rs3808986, 11q24.3, APLP2, 29217, 9.92E-6]. CNV analyses were performed on 1015 AN cases and 3532 controls. Overall frequencies of common or rare CNVs were similar between cases and controls. Specific rare and large (>500 kb, <1%) CNVs of interest included deletion of a large (~1.4Mbp) region of chr13q12 found in 2 AN samples and at a 10 fold lower frequency in a large sample (72,918) of subjects containing the genes SGCG, SACS, TNFRSF19, MIPEP, PCOTH, C1QTNF9B, SPATA13, MIR2276, and C1QTNF9, and an overlapping deletion and a duplication observed in 3 AN samples overlapping the CNTN6 and CNTN4 genes. Partially overlapping ~ 30 kb duplications were seen in 12 AN cases and in 1 control at the CDC5L gene on chromosome 6. Partially overlapping deletion of the 3' half of the PSTPIP1 gene was seen in 5 AN cases and no controls. Finally, a ~ 60 kb deletion of the PLEC1 gene was observed in 5 AN cases and in none of 3532 controls. Discussion: This is the first GWAS of AN. These preliminary results are consistent with absence of a major gene effect in AN. These results are consistent with genetic risk conveyed by multiple common alleles of small effect, as well as some uncommon CNVs of potentially larger effect. None of the implicated genes has a clear role in eating behavior. It must be emphasized that these results are preliminary and an additional ~ 400 AN cases will be analyzed as time and resources permit. These results require confirmation through study of independent populations of AN women.

  Study phs000679

• RNA Sequencing Analysis of Patient-Derived Xenograft Tissue PIM-084 Treated with L-NMMA+Alpelisib vs Vehicle Control

  This dataset contains RNA-seq analysis of vehicle control compared to L-NMMA+alpelisib treated metaplastic breast cancer PDX PIM084 tumors (RNA sequencing and analysis performed by Novogene). The submitted data contains the gene ID, gene name, normalized read counts from all samples from control group and combination treatment group, log2-fold change derived from DESeq2 R/EdgeR package, p-value, adjusted p-value, read counts from each group, and gene FPKM from the each sample in the group. Due to patient privacy, we are submitting only the processed and desensitized RNA sequencing analysis to this repository.

  Study phs003814