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• UK10K NEURO ASD GALLAGHER

  In the UK10K project we propose 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 analyse directly 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. This is an Irish sample set of individuals with ASD (approximately 50% with comorbid intellectual disability). Individuals have been diagnosed with ADI/ ADOS, measures of cognition/ adaptive function. They represent a more severe, narrowly defined cohort of ASD subjects. Family histories are available for some with measures of broader phenotype. For further information on this cohort please contact Nadia Bolshakova (bolshakn@tcd.ie).

  Study EGAS00001000112

• Extensive and differential platinum chemotherapy mutagenesis in livers of children - WGS cell lines

  Whole genome sequencing of HepG2 and THP-1 cell lines. They are untreated vehicle controls for the platinum experiment

  Dataset EGAD00001016141

• Characterization of Cell Free Plasma Methyl-DNA From Xenografted Tumors to Guide the Selection of Diagnostic Markers for Early-Stage Cancers

  Circulating cell-free methyl-DNA (mcfDNA) contains promising cancer markers but its low abundance and possibly diverse origin pose challenges toward the accurate diagnosis of early stage cancers. By whole-genome bisulfite sequencing (WGBS) of cell-free DNA (cfDNA) from about 0.5 mL plasma of mice xenografted with human tumors, we obtained and aligned the reads to the human genome, filtered out the mouse and carrier bacterial sequences, and confirmed the tumor origin of methyl-cfDNA (mctDNA) by methylation-sensitive restriction enzyme digestion prior to species-specific PCR. We estimated that human tumor-specific reads (ctDNA) or mctDNA comprised about 0.29 or 0.01%, respectively of the xenograft mouse cfDNA, and about 0.029 or 0.001% of the cfDNA of human early stage cancer patients. Similar WGBS of early stage (0-II, node- and metastasis-free) breast, lung or colorectal cancer samples identified hundreds of specific DMRs (differentially methylated regions) compared to healthy controls. Their association with tumourigenesis was supported by stage-dependent methylation, tumor suppressor or oncogene clusters, and genes also identified in the xenograft samples. Using 20 three-cancer-common and 17 colorectal cancer-specific DMRs in combination (top 0.0018% of the WGBS methylation clusters) was sufficient to distinguish the stage I colorectal cancers from breast and lung cancers and healthy controls. Our data thus confirmed the tumor origin of mctDNA by sequence specificity, and provide a selection threshold for authentic tumor mctDNA markers toward precise diagnosis of early stage cancers solely by top DMRs in combination. Biological Materials were provided by the Ontario Tumour Bank, which is funded by the Ontario Institute for Cancer Research Reference for citation: Ling Liu, Jinghua Feng, Julian Polimeni, Manli Zhang, Hai Nguyen, Urmi Das, Xu Zhang, Harminder Singh, Xiao-Jian Yao, Etienne Leygue, Sam K.P. Kung, and Xie J. Characterization of cell free plasma methyl-DNA from xenografted tumours to guide the selection of diagnostic markers for early-stage cancers. Frontiers in Oncology, 2021 Feb. 5. DOI: 10.3389/fonc.2021.615821.

  Study EGAS00001006175

• A spatiotemporal cancer cell trajectory underlies glioblastoma heterogeneity

  Abstract: Cancer cells display highly heterogeneous and plastic states in glioblastoma, an incurable brain tumour. However, how these malignant states arise and whether they follow a tractable cellular trajectory across tumours is poorly understood. Here, we generated a deep single cell and spatial multi-omic atlas of human glioblastoma that pairs transcriptomic, epigenomic and genomic profiling of 12 tumours across multiple regions. We identify that glioblastoma heterogeneity is driven by spatially-patterned transitions of cancer cells from developmental-like states towards those defined by a glial injury response and hypoxia. This cancer cell trajectory regionalizes tumours into distinct tissue niches and manifests in a conserved manner across tumours as well as genetically distinct tumour subclones. Moreover, using a new deep learning framework to jointly map cancer cell states and clones in situ, we show that tumour subclones are finely spatially intermixed through glioblastoma tissue niches. Finally, we show that this cancer cell trajectory is intimately linked to myeloid heterogeneity and unfolds across regionalised myeloid signalling environments. Our findings define a stereotyped trajectory of cancer cells in glioblastoma and unify glioblastoma tumour heterogeneity into a tractable cellular and tissue framework.

  Dataset EGAD00001015516

• Longitudinal Study of the Porphyrias

  This is an observational, longitudinal study of approximately 800 individuals with various types of porphyria. Those participants will be evaluated annually for 5 years, or longer if they agree. Participation in this project will include: Participating in annual visits or contacts. Providing samples, including blood, buccal cells (cells from inside of the mouth), saliva, and urine. The type of samples and amounts may vary from person to person, depending on the type of porphyria. Giving permission for samples to be stored and used for porphyrias research. Granting permission to obtain your medical records. Providing information about your medical history and family history. Completing a questionnaire about your porphyria symptoms and quality of life.

  Study phs001278

• The clinical utility of genomics in childhood cancer extends beyond targetable mutations

  Survival of children with relapsed cancer remains unacceptably low. Cancer genomic profiling may identify new therapeutic options, enhance diagnostic accuracy, and improve understanding of tumors’ origins and continued evolution. We deeply sequenced 864 cancer-associated genes and the complete genomes and transcriptomes for 300 pediatric and adolescent/young adult (AYA) patients with poor prognosis or rare tumors. Using integrative somatic-germline analyses, we assessed the clinical utility of cancer genomics in this population. We analyzed tumor mutational signatures and burden to interrogate the relevance of germline variants in DNA repair genes and the impact of therapeutic exposures on tumor evolution. We also evaluated the frequency of changes to tumor drivers and therapeutic targets at relapse in those with serial samples. Integrative analysis yielded clinically actionable variants in a majority of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants were of unanticipated timing and type, with many of these derived from the germline. Enrichment in corroborating mutational signature 3 (‘BRCAness’) in patients with germline homologous recombination defects suggests they are drivers of pediatric cancers and potential targets for PARP inhibition. We show that mutation burden, which may in part be driven by prior therapeutic exposures, was significantly elevated in a minority of patients. Over one-third of patients with sequential samples analyzed showed a change in therapeutically-targetable drivers. Comprehensive somatic-germline cancer genomic profiling is useful at multiple points in the care trajectory for pediatric/AYA patients, supporting its integration into early clinical management. Re-biopsy at the time of relapse should be considered, and specific attention to mutational burden is indicated. Defective DNA repair genes in the germline may represent important targetable drivers.

  Study EGAS00001006034

• Breast cancer DNA repair

  Tumors of germline BRCA1/2 mutated carriers show homologous recombination (HR) deficiency (HRD), resulting in impaired DNA double strand break (DSB) repair and high sensitivity to Poly-(ADP-Ribose)-Polymerase (PARP) inhibitors. Although this therapy is expected to be effective beyond germline BRCA1/2 mutated carriers, a robust validated test to detect HRD tumors is lacking. In the present study we therefore evaluated a functional HR assay exploiting the formation of RAD51 foci in proliferating cells after ex vivo irradiation of fresh breast cancers (BrC) tissue: the RECAP test.Methods Fresh samples of 170 primary BrC were analyzed using the RECAP test. The molecular explanation for the HRD phenotype was investigated by exploring BRCA deficiencies, mutational signatures, tumor infiltrating lymphocytes (TILs) and microsatellite instability (MSI).Results RECAP was completed successfully in 148 out of 170 samples (87%). 24 tumors showed HRD (16%), while 6 tumors were HR intermediate (HRi) (4%). HRD was explained by BRCA deficiencies (mutations, promoter hypermethylation, deletions) in 16 cases. Several non-BRCA deficient HRD tumors showed BRCAness mutational signatures, suggesting that they are also bona fide HRD cases. HRD tumors showed an increased incidence of high TIL counts (p=0.023) compared to HR proficient (HRP) tumors and MSI was more frequently observed in the HRD group (2/20, 10%) than expected in BrC (1%) (p=0.017).Conclusion The RECAP test is a robust assay detecting both BRCA1/2 deficient and BRCA1/2 proficient HRD tumors, suggesting that this test identifies approximately 50% more patients that may benefit from PARPi treatment than BRCA gene testing only.

  Study EGAS00001002792

• Finding the way towards the eradication of therapy-related myeloid neoplasms

  Therapy-related neoplasms are directly caused by the drugs used to eradicate a previous cancer. It is well known that a subset of drugs designed to kill cancer cells through DNA-damage-induced apoptosis can intrinsically, as secondary effect, cause DNA-damage in other cells, thus inducing a neoplasm. Those neoplasms have especially bad prognosis. Why are these drugs still in use? Because for many diseases we do not have anything better, at the moment. Approximately 0.5-1% of the kids treated for various types of cancers develop a therapy-related myeloid neoplasm (tMN) as a result of the treatment. Despite having the same origin, their prognostic and molecular features are different from the adult ones, and a complete understanding of the pathogenesis of tMN in children is still missing. A total of 84 paediatrics neoplasms have been profiled by either Whole Genome or Whole Exome sequencing by Jason R. Schwartz and his colleagues, in a collaborative effort guided at the St. Jude Children's hospital, in Memphis. They identified a mean of 28 somatic mutations per patient, a number which is significantly bigger than the number of mutations found in paediatrics primary neoplasms, as depicted in the original paper's figure 1b, shown here. Their sequencing data identified that Ras/MAPK pathway mutations, alterations in RUNX1 or TP53, and KMT2A rearrangements as the most frequent drivers of the disease. Clonal evolution analysis (the comparative study of the behaviour of cells harbouring different mutations) highlighted that, unlike in adults’ tMN, there were not pre-existing leukemic clones, and virtually all mutated cells were found arising as a direct consequence of cytotoxic therapy. This represents yet another important difference between adult and paediatric tMN. This important study have been published in Nature communications in February 2021. The sequencing data have been deposited at EGA under the study number EGAS00001004850. Thanks to this, other researchers around the world could re-use it to uncover more information, integrate and validate their studies. Revealing the molecular features underlying the development of cancers is the only way towards the development of new generation targeted therapies, which will allow us to finally drop the cytotoxic drugs eliciting such unwanted and catastrophic secondary effects as tMN. It is not an overstatement to say that, while improving the treatment of primary tumours, we could entirely eradicate therapy-related neoplasms right from their origin. Looking forward.

  Blog eradication-of-therapy-related-myeloid-neoplasms

• Bulk-RNA Sequencing of high-grade pancreatic and non-pancreatic Neuroendocrine Neoplasms

  Therapeutic decisions in oncology depend on a precise pathological classification of individual neoplasms. Recent years have seen an intensification of research activities aimed at the extraction of clinically relevant information from patient-derived 'omics' data based on Machine-Learning models. However, a comprehensive training of Machine-Learning models requires sufficiently large numbers of training samples, which are usually not available for rare cancer types. The problem is worsened when individual tissues segregate into different cancer subtypes, as their discrimination would require even more training samples. Methods: Here, we report on a new data-augmentation technique to support the training of Machine-Learning models on ‘omics’ data from pancreatic neuroendocrine neoplasms (panNEN). PanNENs display all properties described above: Only about 2-3% of all pancreatic neoplasms are neuroendocrine and they fall into different subtypes with distinctly different prognosis, which makes the precise classification of such samples both difficult and important for therapy decisions. The approach reconstructs a given transcriptome based on healthy pancreatic cell type signatures and creates a Machine-Learning model that integrates the observed reconstruction error and predicted cell type proportions as features. Results: A benchmark of the deconvolution model predictions with the ground-truth found that the model could efficiently predict the sample grading, disease-related patient survival time, and differentiate between different subtypes in four panNEN and one mixed panNEN and non-pancreatic NENs dataset. We compared the predictive performance of the deconvolution-trained model to that of a model trained directly on the transcriptomic data, under inclusion of the Ki-67 classification gold standard biomarker, and found the performances to be comparable. Conclusion: Our approach serves as a data-augmentation technique to facilitate the training of Machine Learning models for rare cancer types via utilization of data from healthy origin. Additionally, the deconvolution results were clinically interpretable and further research can render the deconvolution approach an effective complementary asset for the clinical classification of neoplasms.

  Study EGAS00001004861

• CCDG CVD: VIRGO - Variation in Recover-Role of Gender on Outcomes of Young Acute Myocardial Infarction (AMI) Patients

  The VIRGO study is a four year research project funded by the NHLBI to study young women and men with heart attacks. A total of 2,000 women who are 18 - 55 years of age and a smaller comparison group of 1,000 similarly aged men will be enrolled in this multi-site observational study from approximately 120 different hospitals across the country. Young women have a much greater risk of dying after an acute myocardial infarction (AMI) than similarly aged men. Their mortality risk is markedly higher than that of young men, and limited data on young minority women suggest that they may have the highest risk of any young subgroup. Findings from the small number of published studies of young women with ischemic heart disease suggest that the biology, epidemiology, care, and outcomes of this group are distinct from those of men. To date, there have been no large studies of this population, even as the death toll is comparable to that from breast cancer in this country. This study will help researchers identify key factors that influence recovery from a heart attack and potentially improve the care and outcomes of young women and men with AMI. Specific Aims: To investigate the excess risk in young women with AMI and to identify key demographic, clinical, metabolic, psychosocial, health care delivery, and biological determinants of prognosis, we propose a national, prospective, observational study of 2,000 women who are 55 years or younger with AMI and a smaller comparison group of 1,000 men. Our prior work and preliminary studies indicate that the sex differences are most prominent in this age group and suggest that by 1 year after discharge, there are substantial sex differences in outcomes. We will also develop risk stratification tools that will help clinicians to identify young women with the highest and lowest risk. Specific Aim 1: Determine sex differences in outcomes following AMI. Specific Aim 2: Determine sex differences in the prevalence and prognostic importance of demographic, clinical, and psychosocial risk factors. Specific Aim 3:Determine sex differences in quality of care. Specific Aim 4: Determine sex differences in the prevalence and prognostic importance of selected biochemical biomarkers following AMI. These samples have been whole genome sequenced as part of the NHGRI's Center for Common Disease Genetics at the Broad Institute.

  Study phs001259