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• Exploratory novel biomarker and resistance mechanism of milademetan, an MDM2 inhibitor, in MDM2 amplified intimal sarcoma from an open-label phase 1b/2 trial ���NCCH1806/MK004���

  Amplified Murine double minute 2 (MDM2) is found in > 70% of intimal sarcoma, known as one of the ultra-rare sarcomas. Milademetan (DS3032, RAIN-32) is a novel, specific, small-molecule MDM2 inhibitor that disrupts MDM2 and the tumor suppressor protein p53 interactions in tumor cells. We conducted a phase 1b/2 trial (Trial registration No: JMA-IIA00402) in patients with amplified MDM2 wild-type TP53 intimal sarcoma as a sub-study under the nationwide large registry for rare cancers in Japan (MASTERKEY Project). Eleven patients were enrolled, and ten were included in the efficacy analysis. Two (20%) patients had durable responses for > 15 months. Milademetan provided clinical benefits in patients with amplified MDM2 intimal sarcoma. Predictive biomarkers other than amplified MDM2 and acquired resistance mechanisms for milademetan are unknown. Whole-exome and RNA sequencing analyses of pre-treatment tissue samples were conducted to identify determinants of response. Genomic alterations were analyzed for 10 patients, and gene expression was analyzed for 9 patients using their pre-treatment tissue samples. Targeted sequencing of cell-free DNA (cfDNA) samples (liquid biopsy) was also conducted sequentially at three points [before treatment with milademetan (baseline), at Cycle 2 Day1, and at the time of disease progression] to identify determinants of response and resistance. From whole-exome and RNA sequencing analyses of pre-treatment tissue samples, we could not find any molecular pathways associated with the anti-tumor activity of milademetan. Focusing on 8 genes (CDK4, CDKN2A, CDKN2B, EGFR, ERBB3, MDM2, PDGFRA, TP53) known to be frequently affected in intimal sarcoma and 10 genes (AKT1, ATM, BBC3, CDKN1A, CDKN1C, CHEK2, MDM4, PMAIP1, PPM1D, TWIST1) reported to be associated with MDM2 inhibitor responses; we found that anti-tumor activity correlated with amplified TWIST1 (p-value = 0.028) and negatively with CDKN2A loss (p-value = 0.071). Eight of the 10 patients had their cfDNA collected sequentially at baseline, at Cycle 2 Day1 and disease progression; however, one did not consent to the exploratory analysis study using cfDNA, and one had cfDNA collected at baseline but not at disease progression due to ongoing treatment. Of the eight patients, TP53 mutations in cfDNA were detected in one and five patients at baseline and disease progression, respectively. The cfDNA allele frequency of TP53 mutations increased with disease progression. CDKN2A loss and amplified TWIST1 could be associated with the anti-tumor activity of milademetan in patients with MDM2 amplified intimal sarcoma. Acquired TP53 mutations were detected in sequential liquid biopsies as loss-of-function mutations, and these TP53 mutations might compromise the anti-tumor activity.

  Study JGAS000619

• 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

• Systems biology of Colorectal Cancer

  Colorectal cancer (CRC) is one of the most common cancers in both males and females, and it is perhaps the best understood of all epithelial tumors in terms of its molecular origin. Yet, despite large amount of work that has concentrated on understanding of colon tumorigenesis, we still do not know the full complement of molecular lesions that are individually necessary – and together sufficient – to cause colorectal cancer. Neither do we understand why some specific mutations that are relatively rare in other tumors (e.g. loss of the APC tumor suppressor) are extremely common in colorectal cancer. We propose here to use the tools of systems biology to develop a quantitative and comprehensive model of colorectal tumorigenesis. The model will include identification of cell-type specific and oncogenic pathways that contribute to colon tumorigenesis, and explain in molecular detail how a genotype of an individual CRC leads to activation of downstream genes that drive uncontrolled cell growth. This model will subsequently be used to find novel therapeutic targets, to guide genetic screening to identify individuals with elevated risk for developing CRC, and to classify patients into molecular subgroups to select the treatment combination that is optimal for each patient (personalized medicine). The specific objectives of the SYSCOL project are: 1. Identify genetic markers for individual risk using genotyping and sequencing of constitutional DNA from sporadic and familial CRC cases and controls 2. Identify genes and regulatory elements that contribute to colorectal cancer cell growth 3. Use data from Aims 1-2 to develop a quantitative model for colorectal tumorigenesis 4. Apply the model for identification of high-risk individuals, for molecular classification of the disease, and for identification of novel molecular treatment targets

  Study EGAS00001000854

• 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

• Drug screening of patient-derived organoids from colorectal peritoneal metastases

  Colorectal cancer (CRC) patients with peritoneal metastases (CRPM) have limited treatment options and the lowest CRC survival rates. We trialed the possibility of organoid directed precision treatment for CRPM patients. CRPM organoids (peritonoids) isolated from patients underwent next-generation sequencing and medium-throughput drug panel testing ex vivo to identify specific drug sensitivities for each patient. We measured the utility of such a service including: success of peritonoid generation, time to cultivate peritonoids, reproducibility of the medium-throughput drug testing, and documented changes to clinical therapy as a result of the testing. Peritonoids were successfully generated and validated from 68% (19/28) of patients undergoing standard care. Genomic and drug profiling was completed within 8 weeks and a formal report ranking drug sensitivities was provided to the medical oncology team upon failure of standard care treatment. This resulted in a treatment change for 2 patients, one of whom had a partial response despite previously progressing on multiple rounds of standard care chemotherapy. The barrier to implementing this technology in Australia is the need for drug access and funding for off-label indications. In conclusion, our approach is feasible, reproducible and can guide novel therapeutic choices in this poor prognosis cohort, where new treatment options are urgently needed. This platform is relevant to many solid organ malignancies.

  Study phs002023

• WES Breast Patient-derived Tumor Organoid

  This dataset includes 18 Whole Exome Sequencing (WES) samples from 5 subjects. WES is performed on a matched pair of case/control samples, e.g., tumor/control or organoid/control. For each patient, the same control sample is used for the analysis of tumor and organoid samples. The sample name structure identifies the type of sample: <subjectId>_[TON][12]_[Case|Ctrl]_EX2; where T, O, and N refer to Tumor tissue, Organoid, and control sample, respectively. The number 1 or 2 refers to the specific tissue, and Case and Ctrl indicate a tumor tissue (or organoid) and a control sample, respectively. For example, ICSBCS007_T1_Case_EX2 is the first tumor tissue of subject ICSBCS007; ICSBCS007_O1_Case_EX2 is the tumor organoid derived from that tumor sample, and ICSBCS007_N1_Ctrl_EX2 is the matching control sample. More information can be found in the sample information table.

  Dataset EGAD50000000961

• Transcriptome analysis of a novel human iPSC-derived 3D cortical tissue model - WT, APP KI, Abeta-treated, Abeta/Aducanumab-treated

  Single-cell RNA-seq analysis of human iPSC-derived microglia/astrocytes/neurons in a novel, human in vitro 3D cortical tissue model. Samples include distinct conditions (each as biological duplicates): - wild-type cells from cultures after 1 month (WT_1mo, cell lines: A18, KOLF) and 3 months (WT_3mo, cell lines: SA2, KOLF, A18) of culturing - knock-in cells from cultures carrying three familial AD mutations in the APP gene (Swedish, Iberian, Arctic; introduced by CRISPR/Cas9-mediated knock-in) after 3 months of culturing (KI_3mo, cell lines: SA2, A18) - subset of WT 1 month-old samples were exposed to 500nM synthetic Abeta42 for 2 consecutive feeds, and a subset of these subsequently treated with 1µg/ml Aducanumab antibody for 14 days

  Dataset EGAD50000002031

• Total RNA sequencing of 32 chronic lymphocytic leukemia (CLL) patients

  Peripheral blood mononuclear cells (PBMC) of CLL patients were isolated by density-gradient centrifugation over Linfosep (Biomedics, Madrid, Spain). B cells were purified with a CD19+ magnetic-bead system (MidiMACS, Miltenyi Biotec, Bergish Gladbash, Germany) according to the manufacturers’ instructions. Mean B-cell purity was &gt;99% and the mean percentage of CD5+/CD19+ cells after purification was &gt;98%, as measured by flow cytometry. Total RNA was extracted from purified cells in a single step using TriPure Isolation Reagent (Roche Applied Science, Vilvoorde, Belgium).Whole transcriptome sequencing libraries were prepared using the TruSeq Stranded Total RNA Sample Preparation Kit (Illumina). Libraries underwent 2 × 76 bp paired-end sequencing on a HiSeq 2500 instrument (Illumina). The median number of paired-end reads was 60.5 million (range, 49.7-79.7 million).

  Dataset EGAD00001004047

• Variant calls for "Quality of Whole Genome Sequencing from Blood versus Saliva Derived DNA in Cardiac Patients"

  Paired blood and saliva samples from five unrelated individuals were directly compared for quality of whole genome sequencing. Two (Sample Pairs 1 and 2) were female probands diagnosed with tetralogy of Fallot, a type of congenital heart disease, and three (Sample Pairs 3, 4 and 5) were male probands diagnosed with hypertrophic cardiomyopathy. WGS was performed using Illumina HiSeq X to a target average coverage depth of 30x and a read length of 150 bp. The resulting reads were not filtered for minimum quality in order to avoid losing possible contaminant reads. Sequencing read alignment was done using Isaac Aligner to human genome build hg19. Short variant i.e. single-nucleotide variant (SNV) and small insertion-deletion (indel) calling was performed using Isaac Variant Caller with default parameters.

  Dataset EGAD00001005772

• Resequencing candidate genes for male spermatogenic impairment

  This study aims to identify novel candidate variants from human Y-chromosomal genes DAZ, BPY2 and CDY1/2 by resequencing the coding regions of these genes from male patients with spermatogenic impairment. The coding regions of the genes plus a selection of phylogenetically informative Y-chromosomal markers have been amplified by standard PCR, amplicon lengths range from 178 to 486 bp. Amplicons were quantified by gel electrophoresis and pooled in approx. equimolar concentrations per patient. For each of the 480 submitted samples, approx. 1 microgram of amplified DNA pool was provided in a total volume of 120 microlitres. The samples were indexed and libraries prepared for PE250bp Illumina MiSeq runs. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ .

  Dataset EGAD00001006784