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• Are children born after medical assisted reproduction at greater risk of having an increased de novo mutation rate?

  Introduction: De novo mutations (DNMs) play a prominent role in sporadic disorders with reduced fitness such as infertility and intellectual disability. Advanced paternal age is known to increase disease risk in offspring by increasing the number of DNMs in their genome. Less is known about the effect of assisted reproduction techniques (ART) on the number of DNMs in offspring. With the on-going trend of delayed parenthood more children are now born both from older fathers and through ART. Materials and Methods: We investigated 49 trios (mother, father and child) and 2 quartets (mother, father and 2 siblings) divided into children born after spontaneous conception (n=18); born after in vitro fertilisation (IVF) (n=17) and born after intracytoplasmic sperm injection combined with testicular sperm extraction (ICSI-TESE) (n=18). Groups further divided by paternal age, young (<35) or old (>45 years of age at conception). Whole-genome sequencing was performed twice to independently detect and validate all DNMs in children. Results: A clear paternal age effect was observed, with 70 DNMs detected on average in children born to young fathers and 94 DNMs in those born to older fathers (p = 0.001). No significant differences were observed between different methods of conception (p = 1) with paternal age affecting all methods equally. Conclusions: Paternal age, not method of conception, had a major effect on the observed number of DNMs in offspring. Given the role DNMs in disease risk, this negative result is good news for IVF and ICSI-TESE born children, if replicated in larger cohorts.

  Study EGAS00001005569

• The University of Hong Kong Gastric Cancer Organoids RHO Signaling Study

  Objective: Cell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells. Design: We explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix, or both, to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAP fusions, RHOA, and CDH1, in modulating CC (CCi) or CM (CMi) adhesion independence. Results: 97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to 3 public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOA mutation or ARHGAP fusions. Inducible knockout of ARHGAP fusions in CCi/CMi tumour organoids led to re-sensitization to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype, and inhibited xenograft formation. Normal gastric organoids engineered with CDH1 or RHOA mutations became CMi or CCi, respectively. Conclusions: The CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

  Study EGAS00001006252

• Regenerative effects of MSC treatment on busulfan-induced small intestine damaged organoids.

  Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Second-line available therapies are immunosuppressants or mesenchymal stromal/stem cell (MSC) infusions. Data from our institution and others demonstrate rescue of approximately 40-50% of patients suffering from aGvHD with mesenchymal stromal/stem cells (MSCs) and minor side effects. Although promising, the better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment. Here, we developed a novel 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapy-mediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating EMT, proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The co-culture of busulfan treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis. Collectively, we demonstrate that our novel in vitro co-culture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium.

  Study EGAS00001007432

• MethylationEPIC BeadChip samples of pre- and post-5ZA-treated head and neck cancer patients refractory to anto-PD-1 therapy

  Background Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with head and neck squamous cell carcinoma (HNSCC); however, most patients are refractory. Methods In a non-randomized, open-label phase 1b clinical trial, participants with recurrent and/or metastatic (R/M) HNSCC were treated with low-dose 5’azacytidine (5’aza) daily for either 5- or 10-days in combination with fixed doses of durvalumab and tremelimumab after progression on ICB therapy. The primary objective was to assess the biologically effective dose of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsies; the secondary objective was safety. Results Thirty-eight percent (3/8) of participants with evaluable paired tissue samples had a greater than 2-fold increase from baseline in interferon-gamma (IFN-ɣ) signature and CD274 (programmed cell death protein 1 ligand, PD-L1) expression within the tumor microenvironment (TME), which was associated with increased CD8+ T cell infiltration and decreased infiltration of CD4+ T regulatory cells. The mean neutrophil-to-lymphocyte ratio (NLR) decreased by greater than 50%, from 14.2 (SD 22.6) to 6.9 (SD 5.2). Median overall survival (OS) was 16.3 months (95% CI 1.9, NA) and 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%) with 58% (7/12) of treated participants demonstrated prolonged OS of greater than 12 months. Conclusion Our findings suggest that low-dose 5’aza can reprogram systemic host immune responses and the local TME to increase IFN-ɣ and PD-L1 expression. The increased expression of these established biomarkers correlated with prolonged OS upon re-challenge with ICB.

  Study EGAS00001007998

• Molecular Phenotyping to Accelerate Genomic Epidemiology (MolPAGE)

  MolPAGE is an integrated EU project that aims to develop methods and tools for discovery of biomarkers associated with diabetes (see www.ocdem.ox.ac.uk for MolOBB and www.twinsuk.ac.uk for MolTWIN).

  Study EGAS00000000102

• Single-cell multi-omic analysis of control and glioblastoma samples from the brain and border regions.

  Single-cell RNA-sequencing. Some samples were analyzed using CITE-Seq and samples were multiplexed and run on the same 10X reaction

  Dataset EGAD50000000045

• IMSGC and MultipleMS project MS patients from Germany, Mainz

  Genotype and phenotype data on 301 MS patients from Germany, Mainz. All individuals were whole-genome genotyped on the Illumina Global Screening Array and files are provided in plink2 format (pgen / pvar / psam files). Provided phenotypes are sex, year of birth, age and Age Related Multiple Sclerosis Severity (ARMSS) score.

  Dataset EGAD00010002484

• IMSGC and MultipleMS project MS patients from Italy, OSR

  Genotype and phenotype data on 538 MS patients from Italy, OSR. All individuals were whole-genome genotyped on the Illumina Global Screening Array and files are provided in plink2 format (pgen / pvar / psam files). Provided phenotypes are sex, year of birth, age and Age Related Multiple Sclerosis Severity (ARMSS) score.

  Dataset EGAD00010002486

• IMSGC and MultipleMS project MS patients from Germany, TUM

  Genotype and phenotype data on 683 MS patients from Germany, TUM. All individuals were whole-genome genotyped on the Illumina Global Screening Array and files are provided in plink2 format (pgen / pvar / psam files). Provided phenotypes are sex, year of birth, age and Age Related Multiple Sclerosis Severity (ARMSS) score.

  Dataset EGAD00010002489

• IMSGC and MultipleMS project MS patients from Italy, Piedmont

  Genotype and phenotype data on 1067 MS patients from Italy, Piedmont. All individuals were whole-genome genotyped on the Illumina Global Screening Array and files are provided in plink2 format (pgen / pvar / psam files). Provided phenotypes are sex, year of birth, age and Age Related Multiple Sclerosis Severity (ARMSS) score.

  Dataset EGAD00010002490