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• BLUEPRINT Epigenetic characterization of megakaryocytes and erythroblasts

  Megakaryocytes and erythroblasts derive from the same progenitor cell type but carry out very different functions. In order to understand how the different functional phenotypes arise we have characterised the epigenetic landscape of these cells.

  Study EGAS00001001641

• Mutational Landscape of Grey Zone Lymphoma

  The mutational landscape of grey zone lymphoma (GZL) has not yet been established and differences to related entities are mostly unknown. Here, we studied coding sequence mutations of 50 EBV-negative GZL and 20 polymorphic EBV-positive DLBCL NOS (poly-EBV-L) in comparison to classical Hodgkin lymphoma (cHL), primary mediastinal B cell lymphoma (PMBCL), and diffuse large B cell lymphoma (DLBCL). Paired exomes of 21 GZL and 7 poly-EBV-L cases were analyzed as a discovery cohort followed by targeted sequencing of 217 genes in an extension cohort of 29 GZL and 13 poly-EBV-L cases. GZL cases with thymic niche involvement displayed a mutation profile closely resembling cHL and PMBCL, with SOCS1 (45%), B2M (45%), TNFAIP3 (35%), GNA13 (35%) and NFKBIA (29%) being the most recurrently mutated genes. In contrast, GZL cases without thymic niche involvement (N=18) had a significantly distinct pattern, enriched in mutations related to apoptosis defects (TP53 (39%), BCL2 (28%), BIRC6 (22%)) and depleted in GNA13, XPO1 or NFKB signaling pathway mutations (TNFAIP3, NFKBIE, IKBKB, NFKBIA). Poly-EBV-L cases presented a distinct mutational profile including STAT3, PRKDC mutations and a significantly lower coding-mutation load in comparison to EBV-negative GZL. Our study highlights characteristic mutational patterns in GZL associated with presentation in the thymic niche suggesting a common cell of origin and disease evolution with related anterior mediastinal lymphomas.

  Study EGAS00001004482

• UK10K NEURO IOP COLLIER

  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. The Genetics and Psychosis (GAP) set consists of samples from subjects with schizophrenia, ascertained as a new-onset sample. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes. The Maudsley twin series consists of probands ascertained from the Maudsley Twin Register, defined as patients of multiple birth who had suffered psychotic symptoms. This set is of UK origin, with data on cognition, brain imaging and other endophenotypes, with DNA available from an MZ or DZ affected or unaffected co-twin. The Maudsley family study (MFS) consists of over 250 families who have a history of schizophrenia or bipolar disorder Within the Maudsley Family Study, biological markers of psychosis include neuropsychological tests, Evoked Response Potentials Tests (ERPs), MRI scans, dermatoglyphics and eye tracking. Early risk factors for psychosis and clinical symptoms are also investigated. This set is of UK origin, with DNA available from both affected and unaffected relatives in many of the probands. For further information on this study please contact David Collier (david.collier@kcl.ac.uk).

  Study EGAS00001000121

• Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

  Untreated prostate cancers rely on androgen receptor (AR) signaling for growth and survival, forming the basis for the initial efficacy of androgen deprivation therapy (ADT). Yet, the disease can relapse and progress to a lethal stage termed castration-resistant prostate cancer (CRPC). Reactivation of AR signaling represents the most common driver of CRPC growth and next generation AR signaling inhibitors (ARSIs) are now used in combination with ADT as a first line therapy. However, ARSIs can result in selective pressure generating AR-independent tumors. The transition from AR-dependence frequently accompanies a change in phenotype resembling developmental trans-differentiation or ‘lineage plasticity’. Neuroendocrine prostate cancer, which lacks a defined pathologic classification, is the most studied type of lineage plasticity. However, most AR-null tumors do not exhibit neuroendocrine features and are classified as ‘double-negative prostate cancer’, the drivers of which are poorly defined. Lineage plasticity studies in CRPC are limited by the lack of genetically defined patient-derived models that recapitulate the disease spectrum. To address this, we developed a biobank of organoids generated from patient biopsies to study the landscape of metastatic CRPC and allow for functional validation assays. Proteins called transcription factors (TFs) are drivers of tumor lineage plasticity. To identify the key TFs that drive the growth of AR-independent tumors, we integrated epigenetic and transcriptomic data generated from CRPC models. By presenting a map of the chromatin accessibility and transcriptomic landscape of CRPC using a diverse biobank of organoids, PDXs and cell lines that recapitulate the heterogeneity of metastatic prostate cancer, we validate CRPC-AR and CRPC-NE subtypes and reveal two subtypes of AR-negative/low samples as well as their respective masterTFs. Additional analysis revealed a model in which YAP, TAZ, TEAD and AP-1 function together and drive oncogenic growth in CRPC-SCL samples. Overall, we show here how an approach to stratify CRPC patients into four subtypes using their transcriptomic signatures can potentially inform upon appropriate clinical decisions.

  Study EGAS00001006059

• Direct Transposition of Native DNA for Sensitive Multimodal Single-Molecule Sequencing

  STUDY GOALS: This study focuses on elucidating the epigenetic modulators of prostate cancer progression and metastasis at high resolution. This is achieved by applying a novel, high-sensitivity single molecule sequencing assay that measures chromatin state on single DNA molecules (SMRT-Tag) to matched primary and metastatic tumor samples from the same patient. Samples are obtained from patient derived xenograft (PDX) models. STUDY DESIGN: Individuals diagnosed with primary and metastatic prostate cancer in the course of routine care were consented and enrolled, and biopsies of primary and/or metastatic lesions performed to obtain sample material used for generating PDX models. Samples collected from these models were processed with a novel strategy developed for highly-sensitive multimodal profiling of single chromatin fibers using the third generation long-read sequencing. The resulting data indicates genetic variants, chromatin organization, and m5dCpG methylation status across the genome. PRINCIPLE FINDINGS: We determined characteristic single-molecule patterns of chromatin organization (spacing of nucleosomes, presence and absence of m5dCpG marks, etc.) that were altered in the transition from primary malignancy to metastasis. Broadly, global chromatin organization was severely disrupted in metastatic samples, resulting in increased accessibility at CTCF motifs, which may be relevant for disease progression. We further identified specific genomic domains including constitutive heterochromatin significantly enriched for irregular or hyper-accessible chromatin. Together, these findings suggest the involvement of ATP-dependent chromatin remodelers in evicting nucleosomes as a facet of metastatic prostate cancer. DATA AVAILABILITY: SAMOSA-Tag, the assay used in this study, is a sequencing assay that uses the third generation long read sequencing, specifically the SMRT sequencing platform from Pacific Biosciences. Demultiplexed raw SMRT sequencing BAM files generated in this study are deposited. Individual raw subread BAM files correspond to replicate sequencing assays performed on either primary or metastatic PDX prostate tumors.

  Study phs003511

• Early Methamphetamine Abstinence: fMRI and Brain Function

  This study included two groups of subjects, methamphetamine-dependent and healthy control participants, with the purpose of characterizing brain structure and cognition during the first month of abstinence from methamphetamine. Participants were able to participate in one or both phases of the study. Methamphetamine abusers were held as inpatients and abstained from methamphetamine use during the entirety of the study. Phase I covered the 1st week of abstinence and Phase II covered the next 3-4 weeks of abstinence. Control subjects participated as outpatients at timeframes which corresponded to the assessments taken of methamphetamine users. The following outlines the procedures in more detail. After initial telephone screening, in-person screening and recruitment procedures took place at the UCLA Neuropsychiatric Institute. Each methamphetamine abuser subject entered the study after completing an interview and questionnaires on drug use history, and providing a positive urine test for methamphetamine. The evaluation included a psychiatric diagnostic interview according to the Structured Clinical Inventory for DSM-IV (SCID-IV), a medical history and physical examination, blood tests [including a complete chemistry panel, hepatic panel, and tests for hepatitis-C and HIV]. Urine samples were also taken for drug screening of illicit drugs, and to test for pregnancy (female subjects). The methamphetamine abusers were then admitted to the General Clinical Research Center (CRC) and participated on a residential basis, where they were administered daily questionnaires about drug craving, withdrawal and mood. The current study makes available phenotype and genotype data, and interested investigators may contact the principal investigator regarding potential sharing of fMRI data.

  Study phs001198

• Somatic mutation and clonal evolution normal breast tissue WGS

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development. . This dataset contains all the data available for this study on 2023-03-09.

  Dataset EGAD00001010123

• Somatic mutation and clonal evolution normal breast tissue TGS (2020-01-15)

  Cancer is a genetic disease caused by an accumulation of mutations, however many of these mutations have been identified in pathologically normal tissue. We aim to use laser-capture microscopy (LCM) to sample individual clones from breast tissue to identify whether cancer-associated mutations appear in this normal tissue, assess the mutational burden present, and identify the mutational processes causing these mutations. We will sample from a wide age range of individuals (<20 to >70 years old) to determine whether these processes differ in pre- and post-menopausal women. We will also be comparing the tissue from healthy individuals (samples from breast reduction surgery) to those at elevated risk of breast cancer (mastectomy from BRCA1/2 patients) and those who have breast cancer (adjacent normal, distal normal, and tumour tissue from mastectomy). This will allow us to determine how these processes are different between these groups of individuals, and gain insight into the earliest stages of tumour development. . This dataset contains all the data available for this study on 2020-01-15.

  Dataset EGAD00001005787

• ctDNA to predict risk of progression and death after trifluridin/tipiracil therapy

  Background. Late-line treatment in metastatic colorectal cancer (mCRC) can improve the prognosis. However, not every patient has a benefit and may experience severe side effects. Thus, predictive/prognostic biomarkers are urgently needed. Despite many promising results, the role of circulating tumor DNA (ctDNA) analysis in trifluridin/tipiracil (FTD/TPI) treated mCRC patients is so far still elusive. Study design. This prospective non-interventional translational biomarker phase II study enrolled 30 metastatic CRC patients treated with FTD/TPI. The primary study aim was to identify a molecular biomarker to predict overall survival (OS) benefit upon FTD/TPI treatment. Methods. mCRC patients (60% male, 40% female) with FTD/TPI therapy were included. Molecular profiling in cell-free DNA from plasma was performed prior to treatment and on average 4, 8 and 12 weeks after FTD/TPI initiation. Tumor levels were assessed as the highest variant allele frequency (hVAF) and correlated with OS. Uni- and multivariate analyses for survival were performed with clinical variables. Multivariate analyses for survival and treatment efficacy were adjusted to age, gender and ECOG performance status. Results. Compared to previous data, our disease control rate of 30% was lower with a median OS of 8.1 months and a median PFS of 3.2 months. At baseline (BL) and the first two follow-ups (FU), a hVAF cut-off of 7.5% was most discriminative (BL HR 0.39 95% CI 0.16 - 0.98 P=0.0212, FU1 HR 0.30 95% CI 0.12 -0.77 P=0.0021, FU2 HR 0.23 95% CI 0.08-0.70 P=0.0004) whereas at the last follow-up the stratification was most pronounced at a 15% cut-off. An elevated hVAF trajectory over time was associated with a higher risk of death. Conclusion. ctDNA is detectable in a high proportion of mCRC patients. Changes in ctDNA levels are associated with survival among FTD/TPI therapy and may identify patients who benefit most from treatment in these late-stage disease.

  Study EGAS00001006883

• The subclonal architecture of metastatic breast cancer: Results from a prospective community-based rapid autopsy program 'CASCADE'

  Background: Understanding the cancer genome is seen as a key step in improving outcomes for cancer patients. Genomic assays are emerging as a possible avenue to personalised medicine in breast cancer. The majority of work in this area has targeted primary tumours however, and very few studies have performed comprehensive profiling of advanced disease. Evolution of the cancer genome during the natural history of breast cancer is largely unknown, as is the profile of disease at death. We sought to study in detail these aspects of advanced breast cancers that have resulted in lethal disease. Methods and Findings: Three patients with ER-positive, HER2-negative breast cancer and one patient with triple negative breast cancer underwent rapid autopsy as part of an institutional prospective community-based rapid autopsy program. Cases represented a range of management problems in breast cancer, including late relapse after early stage disease; de novo metastatic disease; discordant disease response and disease refractory to treatment. Between 5 and 12 metastatic sites were collected at autopsy together with available primary tumours and longitudinal metastatic biopsies taken during life. Samples underwent paired tumour-normal whole exome sequencing and single nucleotide polymorphism arrays. Subclonal architectures were inferred by jointly analysing all samples from each patient. Mutations were validated using high depth amplicon sequencing.Between cases, there were significant differences in mutational burden, driver mutations, mutational processes and copy number variation. Within each case, we found dramatic heterogeneity in subclonal structure from primary to metastatic disease and between metastatic sites, such that no single lesion captured the breadth of disease. Metastatic cross seeding was found in each case and treatment drove subclonal diversification. Subclones displayed parallel evolution of treatment resistance in some cases, and apparent augmentation of key oncogenic drivers as an alternative resistance mechanism. We also observed the key role of mutational processes in subclonal evolution.Limitations of this study include the potential for bias introduced by joint analysis of formalin fixed archival specimens with fresh specimens, and the difficulties in resolving subclones with whole exome sequencing. Other alterations that could define subclones such as structural variants or epigenetic modifications were not assessed. Conclusions: This study highlights the variety of mechanisms that shape the genome of metastatic breast cancer, and the value of studying advanced disease in detail. Treatment drives significant genomic heterogeneity in breast cancers which has implications for disease monitoring and treatment selection in the personalised medicine paradigm.

  Study EGAS00001002153