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• BARIA baseline first 100 individuals transcriptomes

  Prevalence of obesity and associated diseases, including type 2 diabetes mellitus, dyslipidaemia and non-alcoholic fatty liver disease (NAFLD), are increasing. Underlying mechanisms, especially in humans, are unclear. Bariatric surgery provides the unique opportunity to obtain biopsies and portal vein blood-samples. Methods The BARIA Study aims to assess how microbiota and their metabolites affect transcription in key tissues and clinical outcome in obese subjects and how baseline anthropometric and metabolic characteristics determine weight loss and glucose homeostasis after bariatric surgery. We phenotype patients undergoing bariatric surgery (predominantly laparoscopic Roux-en-Y gastric bypass), before weight loss, with biometrics, dietary and psychological questionnaires, mixed meal test (MMT) and collect fecal-samples and intra-operative biopsies from liver, adipose tissues and jejunum. We aim to include 1500 patients. A subset (approximately 25%) will undergo intra-operative portal vein blood-sampling. Fecal-samples are analyzed with shotgun metagenomics and targeted metabolomics, fasted and postprandial plasma-samples are subjected to metabolomics, and RNA is extracted from the tissues for RNAseq-analyses. Data will be integrated using state-of-the-art neuronal networks and metabolic modeling. Patient follow-up will be ten years.

  Study EGAS00001005704

• A Single-cell Atlas of Progressive TKI Resistance in Chronic Myeloid Leukemia

  High-dimensional scRNA seq and CyTOF were used to identify features predictive of treatment outcome at diagnosis. An optimal TKI response was characterised by erythroid lineage skewing of the CD34+ HSPC compartment. While TKI-resistant CP was reminiscent of a BC-like state, where HSPCs were enriched for inflammation, stemness and quiescence. We designed a machine-learning approach which assessed the prognostic potential of all 32 sub-populations of our scRNA seq dataset. LSCs and NK populations harboured the highest prognostic power at diagnosis. Within the LSCs, erythroid lineage priming and MYC activation were features of an optimal and poor TKI responses, respectively. With the NK cell compartment, apart from a higher abundance of NK cells in TKI optimal responders, a memory-like HLA-DR+ adaptive NK and KLRC1+ NK populations were hallmarks of an optimal and poor TKI responses, respectively. Mechanistically, both cell intrinsic and extrinsic mechanisms contributed towards the higher sensitivity of EPs to TKI therapy. In summary, our high-dimensional single-cell atlas of TKI resistance highlights pivotal transcriptional features associated with TKI-resistance disease, some of which have the potential to be exploited as biomarkers.

  Study EGAS00001005509

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001005784

• Clonal Decomposition and DNA Replication States Defined by Scaled Single-Cell Genome Sequencing

  Accurate measurement of clonal genotypes, mutational processes, and replication states from individual tumor-cell genomes will facilitate improved understanding of tumor evolution. We have developed DLP+, a scalable single-cell whole-genome sequencing platform implemented using commodity instruments, image-based object recognition, and open source computational methods. Using DLP+, we have generated a resource of 51,926 single-cell genomes and matched cell images from diverse cell types including cell lines, xenografts, and diagnostic samples with limited material. From this resource we have defined variation in mitotic mis-segregation rates across tissue types and genotypes. Analysis of matched genomic and image measurements revealed correlations between cellular morphology and genome ploidy states. Aggregation of cells sharing copy number profiles allowed for calculation of single-nucleotide resolution clonal genotypes and inference of clonal phylogenies and avoided the limitations of bulk deconvolution. Finally, joint analysis over the above features defined clone-specific chromosomal aneuploidy in polyclonal populations.

  Study EGAS00001003190

• Targeted sequencing of diffuse large B-cell lymphoma tumour samples from the UK's Haematological Malignancy Research Network

  The UK’s Haematological Malignancy Research Network (www.HMRN.org) was established in 2004 to provide robust generalizable data to inform clinical practice and research. HMRN is a collaboration between researchers in the Epidemiology & Statistics Group (ECSG) at the University of York, a unified Clinical Network operating across 14 hospitals, and an integrated Haematological Malignancy Diagnostic Service (HMDS) in Leeds. Covering a population of around 4 million, HMRN collects detailed information about all patients diagnosed with a haematological malignancy within the HMRN region, accruing around 2,400 new diagnoses each year. The population has a similar socio-demographic profile to the country as a whole, and HMRN’s maturing data present an increasingly valuable resource to address real questions of concern to haematologists, commissioners and health service researchers – locally, nationally and internationally. This study forms part of a larger project employing targeted exome sequencing on tumour samples from patients diagnosed with a variety of both lymphoid and myeloid malignancies. The results for samples collected from 928 diffuse large B-cell lymphoma patients, diagnosed within HMRN from 2005 to 2012, are provided.

  Study EGAS00001005953

• Allele-specific expression of GATA2 due to epigenetic dysregulation in double mutated CEBPA AML

  Transcriptional deregulation is a central event in the development of acute myeloid leukemia (AML). To identify potential disturbances in gene regulation, we conducted an unbiased screen of allele-specific expression (ASE) in 209 AML cases. The gene encoding GATA binding protein 2 (GATA2) displayed ASE more often than any other myeloid or cancer-related gene. GATA2 ASE was strongly associated with CEBPA double mutations (CEBPA DM), with 95% of cases presenting GATA2 ASE. In CEBPA DM AML with GATA2 mutations, the mutated allele was preferentially expressed. We found that GATA2 ASE is a somatic event lost in complete remission, supporting the notion that it plays a role in CEBPA DM AML. Acquisition of GATA2 ASE involved silencing of one allele via promoter methylation, compensated by overactivation of the other allele, thereby preserving expression levels. Notably, promoter methylation was also lost in remission together with GATA2 ASE. In summary, we propose that GATA2 ASE is acquired by epigenetic mechanisms and is a prerequisite for the development of AML with CEBPA DM. This finding constitutes a novel example of an epigenetic hit cooperating with a genetic hit in the pathogenesis of AML.

  Study EGAS00001004684

• Genomics-based personalized oncology in cancer of unknown primary (CUP, project H021)

  To perform a comprehensive genomic characterization of 70 patients suffering from cancer of unknown primary (CUP) we used whole-exome, whole-genome, transcriptome and methylome analysis. We detected a substantial mutational heterogeneity with genes most commonly affected by SNVs, indels and fusions being TP53, TTN, MUC16, ABCA13, COL6A3, KRAS, LRP1B, XIRP2 and CSMD3. The most common fusion involved FGFR2, the most common focal deletion affected CDKN2A. A molecular tumor board recommended genomics-based therapies in 56/70 (80%) patients which were applied in 20/56 (35.7%) cases. Entity predictions based on transcriptome and methylome data could be made in up to 62/70 (88.6%) cases but were conclusive in only 16/48 (33.3%) cases. Germline analysis revealed 6 (likely) pathogenic mutations in 5 patients. Recommended therapies translated into a mean PFS2/1 ratio of 3.61 (median=2.25) with a median PFS1 of 89 days (n=17) compared to a median PFS2 of 182.5 days (n=20). Our data emphasize the clinical benefit of comprehensive genetic approaches in diagnostic and therapeutic management and underline the need for innovative, mechanism-based clinical trials in this heterogeneous group of diseases.

  Study EGAS00001004786

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001006306

• PDAC organoid genomic heterogeneity

  The establishment of patient-derived pancreatic cancer organoid culture in recent years creates an exciting opportunity for researchers to perform a wide range of in vitro studies on a model that closely recapitulates the tumor. Among the outstanding questions in pancreatic cancer biology are the causes and consequences of genomic heterogeneity observed in the disease. However, to use pancreatic cancer organoids as a model to study genomic variations, we need to first understand the degree of genomic heterogeneity and its stability within organoids. Here, we used single-cell whole-genome sequencing to investigate the genomic heterogeneity of two independent pancreatic cancer organoids, as well as their genomic stability with extended culture. Clonal populations with similar copy number profiles were observed within the organoids, and the proportion of these clones was shifted with extended culture, suggesting the growth advantage of some clones. However, sub-clonal genomic heterogeneity was also observed within each clonal population, indicating the genomic instability of the pancreatic cancer cells themselves. Furthermore, our transcriptomic analysis also revealed a positive correlation between copy number alterations and gene expression regulation, suggesting the “gene dosage” effect of these copy number alterations that translates to gene expression regulation.

  Study EGAS00001006782

• DNA methylation landscape of prostate cancer

  Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy thanks to improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles are associated with the mutually exclusive SPOP mutant or TMPRSS2-ERG fusion genetic backgrounds. Using a cohort of 42 patients with prostate cancer brain metastases (PCBM), with matched primary samples available for 17 patients, we carried out DNA methylation analysis using Illumina EPIC array. We examined the epigenetic distinction between primary PCa and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM in particular. Multiregion sampling of PCBM revealed epigenetic heterogeneity in metastases. We found aberrant methylation in PCBM is associated with mutational background, PRC2 complex activity and upregulation of EZH2, an effect that is particularly pronounced in SPOP mutant PCBM. While we detected a hypermethylator phenotype in PCBM, we also observed hypomethylation occurring at the promoters of genes involved in neuroactive ligand-receptor interactions or the calcium signalling pathway, such as GABRB3 and GRM5, a change not observed in non-brain prostate cancer metastases.

  Study EGAS00001006670