Search Results - EGA European Genome-Phenome Archive

Epiclomal: probabilistic clustering of sparse single-cell DNA methylation data

We present Epiclomal, a probabilistic clustering method arising from a hierarchical mixture model to simultaneously cluster sparse single-cell DNA methylation data and infer their corresponding hidden methylation profiles. Using synthetic and published single-cell CpG datasets we show that Epiclomal outperforms non-probabilistic methods and is able to handle the inherent missing data feature which dominates single-cell CpG genome sequences. Using a recently published single-cell 5mCpG sequencing method (PBAL), we show that Epiclomal discovers sub-clonal patterns of methylation in aneuploid tumour genomes, thus defining epiclones. We show that epiclones may transcend copy number determined clonal lineages, thus opening this important form of clonal analysis in cancer.

Study EGAS00001003504

Detection and genomic analysis of BRAF fusions in Juvenile Pilocytic Astrocytoma through the combination and integration of multi-omic data

Juvenile Pilocytic Astrocytoma (JPAs) are highly vascular tumors and show pervasive immune infiltration, which can lead to low tumor cell purity in clinical samples. In some instances, this results in gene fusions that are difficult to detect with conventional omics approaches including RNA-Seq. To this effect, we applied RNA-Seq as well as linked-read whole-genome sequencing and in situ Hi-C as new approaches to detect and characterize low-frequency gene fusions at the genomic, transcriptomic and spatial level. Overall, we demonstrate the power of integrating multi-omic datasets to identify low frequency fusions and characterize the JPA genome at high resolution.

Study EGAS00001006388

Time-dependent characterization of CNS response in COVID-19

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 primarily affects the respiratory system, but the observation of diverse neurological symptoms indicates that other organs, including the brain, may be involved. The pathophysiological mechanisms of COVID-19-associated effects on the central nervous system (CNS) have become clearer during the past two years. Nevertheless, the precise CNS-specific molecular mechanisms are still elusive and raise several questions. To further elucidate the host response at brain tissue level, we profiled single-nucleus transcriptomes and performed proteomics from olfactory mucosa, olfactory bulb, medulla oblongata and cerebellum at different timepoints of the disease in individuals who died of COVID-19 and underwent rapid autopsy.

Study EGAS00001006442

T cell reactivity of MHC epitopes

By using >36,000 immunogenicity assay results, we developed a method to identify peptide-MHC complexes whose structural alignment facilitates T cell reaction. Our method accurately predicted neoepitopes for MHC II as well as MHC I that were responsive to checkpoint blockade when applied to &gt;1,200 samples of various tumor types and on-therapy melanoma samples. To investigate selection by spontaneous immunity at the single epitope level, we analyzed the frequency spectrum of &gt;25 million mutations in &gt;9,000 treatment-naïve tumors in association with &gt;100 immune phenotypes. MHC II immunogenicity specifically lowered variant frequencies in tumors under high immune pressure particularly with high TCR clonality and MHC II expression.

Study EGAS00001006445

Multiple Sclerosis risk variants regulate gene expression in innate and adaptive immune cells

Each of at least 200 single nucleotide polymorphisms (SNPs) have been confirmed to be associated with individually small increases in the risk of Multiple Sclerosis (MS). A key function that could mediate SNP encoded MS risk is their regulatory effects on gene expression or splicing. Transcriptomic profiling was performed using Affymetrix gene-expression microarrays, using RNA extracted from purified human peripheral blood monocytes, CD4 and CD8 positive lymphocyte cells, B-lymphocyte cells and Natural Killer cells from 73 untreated MS cases and 97 healthy controls. Cis expression quantitative trait locus (eQTL) mapping studies were performed in each cell type separately to characterize MS risk loci associated with gene expression change.

Study EGAS00001004087

Identification and functional characterisation of a rare MTTP variant underlying familial non-alcoholic fatty liver disease

We identified a rare causal variant in MTTP, c.1691T>C p.I564T (rs745447480) encoding microsomal triglyceride transfer protein (MTP) causing progressive non-alcoholic fatty liver disease with cirrhosis and hepatocellular carcinoma unrelated to metabolic syndrome, without manifestations of abetalipoproteinemia, in a four generation family with South Asian ancestry. Variant-expressing hepatocyte-like-cells (HLCs) derived from human induced pluripotent stem cells generated from homozygous donor skin fibroblasts had lower lipoprotein ApoB secretion, compared to wild type cells. Cytoplasmic triglyceride accumulation in HLCs triggered endoplasmic reticulum stress, secretion of pro-inflammatory mediators, production of reactive oxygen species, delineating the progression of disease associated with homozygosity for MTTP p.I564T

Study EGAS00001005254

Chip_seq_oesophageal_adenocarcinoma_

There is complex interplay between underlying genetic sequence and epigenetic factors, however this interplay is still illusive. Massively reconstructed cancer genomes can be used in order to better understand this relationship. Six oesophageal adenocarcinoma organoids will be sequenced using long read sequencing technologies and will be profiled for a range of epigenetic marks. Combination of genetic and epigenetic data will allow the thorough characterisation of reference cancer genomes and will provide novel insights into mechanisms of gene regulation. Description: Chip-seq Sequencing of 5 patient derived organoid cell models. Each model was derived from a piece of patient tumour taken following surgical rescetion of the tumour. All model derivations took place with the CGaP facility in Sanger.

Study EGAS00001007180

Intra-prostatic tumour evolution, steps in metastatic spread and histogenomic associations revealed by integration of multi-region whole genome sequencing with histopathological features

We performed whole genome sequencing on 42 prostate cancer samples from the prostate, seminal vesicles and regional lymph nodes of five treatment-naive patients with locally advanced disease who underwent radical prostatectomy. Using cancer cell fractions computed from single nucleotide variants and copy number alterations, we reconstructed the tumour phylogenies, which in turn allowed us to infer key molecular steps in the progression of prostate cancer in these individuals. We mapped the clonal composition of cancer sampled across the prostate in each individual and inferred the routes of spread of cancer cells within the prostate and to seminal vesicles and lymph nodes.

Study EGAS00001007438

Genomic profiling of IBC

We collected matched pretreatment blood and tumor samples from 19 patients with primary TN-IBC enrolled in a phase II clinical trial (NCT02876107). Patients were treated with neoadjuvant chemotherapy (NAC) or the anti-EGFR antibody panitumumab (PmAb) plus NAC (PmAb/NAC). We conducted whole-exome sequencing, RNA sequencing, and CIBERSORT analyses for these TN-IBC samples and compare the genetic and molecular profiles with similarly analyzed stage III TN-non-IBC patient samples. We also compared the genetic and molecular characteristics of TN-IBC in patients who had a pathologic complete response (pCR) to NAC or PmAb/NAC treatment, a suitable surrogate endpoint for IBC, with those who did not have pCR (non-pCR).

Study EGAS00001007520

Single-cell RNA-seq of peripheral blood mononuclear cells in classic Hodgkin lymphoma

Classic Hodgkin lymphoma (cHL) is a largely MHC class I-negative tumor with recurrent 9p24.1/ PD-L1/ PD-L2 copy gains and the highest reported response rates to PD-1 blockade. We utilized scRNA sequencing to characterize the peripheral immune response to PD-1 blockade and more broadly define non-CD8+ dependent mechanisms of immune evasion in cHL. Peripheral blood mononuclear cells were obtained from 20 patients with relapsed/refractory (R/R) cHL treated with PD-1 blockade (nivolumab) on the CheckMate 205 clinical trial (paired samples from cycle 1 day 1 [C1D1] and cycle 4 day 1 [C4D1]), 11 patients with newly diagnosed, previously untreated cHL and 13 healthy donors.

Study EGAS00001007569

Genetic landscape of pediatric Medulloblastoma

Medulloblastoma is a heterogenous disease made up of at least four distinct subtypes of disease which appear to exploit and disrupt naturally occurring developmental pathways of cellular growth and hindbrain development. To better understand the driver mutations of this disease, we performed whole genome sequencing of 37 medulloblastomas and the corresponding normal DNA of the 37 affected children treated at St. Jude Children's Research Hospital. We have found several novel mutations which appear subtype specific. These mutations were checked for frequency in a separate tumor cohort of 56 children with medulloblastoma, also treated on the St. Jude Medulloblastoma 2003 trial, and were tested in several animal models of medulloblastoma for proof of oncogenic potential.

Study EGAS00001000347

Comprehensive analysis of the (epi)genome of pediatric atypical teratoid/rhabdoid tumours (AT/RTs)

Whole exome sequencing of atypical teratoid /rhabdoid tumors (AT/RTs) revealed recurrent mutations only in SMARCB1, a gene involved in chromatin remodeling. However, preliminary data from our lab using gene expression and DNA methylation arrays shows that there are three distinct molecular subgroups of AT/RTs, suggesting that other molecular alterations underlying the development of these aggressive pediatric brain tumors must be found outside the coding genome or at the epigenomic level. Identification of these (epi)genomic alterations, which we intend to address in this project, may lead to novel treatment strategies for these tumors and reveal options for meaningful patient stratification.

Study EGAS00001001297

Proteomic Characterization of Intrahepatic Cholangiocarcinoma Identifies Risk-Stratifying Subgroups, Proteins Associated with Time-To-Recurrence, and mTOR Effector Molecule EIF4A1 as a Druggable Therapeutic Target

Using mass spectrometry-based proteomics, we analyzed two independent cohorts comprising 80 and 62 treatment-naive ICC tumors, 67 adjacent non-malignant tissues, and 9 patient-derived xenografts (PDX). In the first cohort, we identifed two subclusters with distinct times-to-recurrence (TTR). A 4-protein classifier trained on our data cohort accurately stratifies these ICC clusters in the Dong et al. dataset (2022) and in our independent second cohort, revealing similar associations between proteomic motifs and clinical outcomes. The Translation regulator EIF4A1 emerges as a therapeutic target, as its inhibition with novel drug eFT226 significantly reduces tumor growth in an ICC PDX model.

Study EGAS50000001343

Targeted de novo phasing and long-range assembly by template mutagenesis

Long-range sequencing with low error rate has been challenging. Sequence assembly and phasing usually require a high-quality reference genome for mapping, so working on highly-variable genomic regions or regions with no reference genome information would be difficult. In this study, we describe novel bench protocols and algorithms to obtain ultra-low-error-rate haplotype-phased sequence assemblies of regions 10 KB in length using a short-read sequencing platform that simultaneously solves the above two problems. We accomplish this by imprinting each template strand from a target region with a dense and unique mutation pattern. The mutation process randomly and independently converts ~50% of cytosines to uracils. Short-read sequencing libraries are made from both mutated and unmutated templates. A conservative de Bruijn graph approach seeds an assembly of the mutated templates, which we then extend by mapping paired-end reads. We next partition the template assemblies into two or more haplotypes after using the unmutated sequence library to recover almost all of the mutated bases. The final haplotype is assembled and corrected for residual template mutations and PCR errors. We obtain per-base-error rates below 10 9. We apply this method to a human family, correctly assembling and phasing three genomic intervals, including the highly polymorphic HLA-B gene.

Dataset EGAD00001008444

Somatic mutation rates scale with lifespan across mammals

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans. Comparative analyses can shed light on the diversity of mutagenesis across species and on long-standing hypotheses regarding the evolution of somatic mutation rates and their role in cancer and ageing. Here, we used whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found somatic mutagenesis to be dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans, although the relative contribution of each signature varied across species. Remarkably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied displaying a comparable association. Despite widely different life histories among the species surveyed, including ~30-fold variation in lifespan and ~40,000-fold variation in body mass, the somatic mutation burden at the end of lifespan varied only by a factor of ~3. These data unveil common mutational processes across mammals and suggest that somatic mutation rates are evolutionarily constrained and may be a determinant of lifespan.

Dataset EGAD00001008032

MutWP4: CRUK Grand Challenge Mutographs of Cancer: Gastric Organoids (2019-08-07)

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2019-08-07.

Dataset EGAD00001005234

Single-cell RNA-sequencing of CD19 Chimeric Antigen Receptor (CAR) T-cells (CD19 CAR T-cells) from a Phase I clinical study in paediatric ALL: CARPALL

Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.

Dataset EGAD00001010018

33 patients with Monoclonal Gammopathy of Undetermined Significance (MGUS)

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant precursor of multiple myeloma (MM) with a 1% risk of progression per year. Although targeted analyses have shown the presence of specific genetic abnormalities such as IGH translocations, RB1 deletion, 1q gain, hyperdiploidy or RAS genes mutations, little is known about molecular mechanism of malignant transformation. We have performed whole exome sequencing together with SNP array analysis in 33 flow-cytometry separated abnormal PC samples of MGUS patients to describe somatic gene mutations and chromosome changes at the genome-wide level. Non-synonymous mutations (NS-SNVs) and copy number alterations (CNAs) were present in 97.0% and in 63.6% of cases, respectively. Importantly, the number of somatic mutations was significantly lower in MGUS compared to MM (p<10-4) and we have identified 6 myeloma significantly mutated genes which are KRAS, NRAS, DIS3, HIST1H1E, EGR1 and LTB in the MGUS dataset. We also found a positive correlation with increasing chromosome changes and somatic mutations. IGH translocations were present in 27.3% of cases comprising t(4;14), t(11;14), t(14;16) or t(14;20) and were in a similar frequency to MM, which corresponded with primary lesion hypothesis. Data from this study showed MGUS is a genetically comprehensive disease, however overall genetic instability is significantly lower compared to MM.

Dataset EGAD00001001901

Extreme phenotypes define epigenetic and metabolic signatures in cardiovascular diseases

Improving the understanding of cardiometabolic syndrome pathophysiology and its relationship with thrombosis are ongoing healthcare challenges. Using plasma biomarkers analysis coupled with the transcriptional and epigenetic characterisation of cell types involved in thrombosis, obtained from two extreme phenotype groups (obese and lipodystrophy) and comparing these to lean individuals and blood donors, the present study identifies the molecular mechanisms at play, highlighting patterns of abnormal activation in innate immune phagocytic cells and shows that extreme phenotype groups could be distinguished from lean individuals, and from each other, across all data layers. The characterisation of the same obese group, six months after bariatric surgery shows the loss of the patterns of abnormal activation of innate immune cells previously observed. However, rather than reverting to the gene expression landscape of lean individuals, this occurs via the establishment of novel gene expression landscapes. Netosis and its control mechanisms emerge amongst the pathways that show an improvement after surgical intervention. Taken together, by integrating across data layers, the observed molecular and metabolic differences form a disease signature that is able to discriminate, amongst the blood donors, those individuals with a higher likelihood of having cardiometabolic syndrome, even when not presenting with the classic features.

Dataset EGAD00001005197

MutWP4: CRUK Grand Challenge Mutographs of Cancer: Pancreatic Organoids (2021-02-02)

The Mutographs project aims to advance our understanding of the causes of cancer through studies of mutational signatures. Led by Mike Stratton, together with Paul Brennan, Ludmil Alexandrov, Allan Balmain, David Phillips and Peter Campbell, this large-scale international research endeavour was awarded a Cancer Research UK Grand Challenge. Different patterns of somatic mutation are generated by the different environmental, lifestyle and genetic factors that cause cancer, many of them are still unknown. Within Mutographs, Kings College London will characterise the mutational signatures induced by putative human carcinogens in order to identify the origins of mutational signatures found in human cancers. To achieve this human organoid cell cultures will be exposed to a representative catalogue of known or suspected human carcinogens and mutagens and, using whole genome sequencing, the patterns of mutations induced by them will be determined. Somatic mutational signatures will be subsequently extracted by non-negative matrix factorisation methods and correlated with exposure data. Through an enhanced understanding of cancer aetiology, Mutographs unprecedented effort is anticipated to outline modifiable risk factors, lead to new approaches to prevent cancer, and provide opportunities to empower early detection, refine high-risk groups and contribute to further therapeutic development. . This dataset contains all the data available for this study on 2021-02-02.

Dataset EGAD00001006933

The mutational landscape of skin tumours in CYLD cutaneous syndrome determined

Patients with germline mutations in CYLD can develop hundreds of benign skin tumours called cylindromas. The development of multiple tumours within a single patient at sun-protected and sun-exposed sites, varying tumour histological patterns and grades of malignancy allow for the testing of several genetic hypothesis in relation to cutaneous carcinogenesis. By adopting the unprecedented approach of whole genome sequencing of multiple benign skin tumours within individuals in multigenerational families, we set out to study the impact of mutational diversity on models such as multistep carcinogenesis as well as non-sequential carcinogenesis. Using non-negative matrix factorisation (NMF) to discover mutational signatures, we found distinct mutational signatures in identical benign tumours (N=2 patients; n=11 tumours) at sun exposed and sun protected skin tumours within a mother and her daughter. We found recurrent mutations in epigenetic modifying genes in CCS tumours which are known to have an oncogenic dependency on Wnt signalling. We also demonstrate that cutaneous tumours that metastasize to the lung carry a a UV signature, supporting the origin from the skin. Distinct malignant tumours, such as BCC and malignant spiradenocarcinoma carried unique driver mutations. These findings add new dimensions to the existing paradigms of UV-induced skin cancer and highlight the utility of studying rare disease to gain novel insights into genetic mechanisms of tumour formation.

Dataset EGAD00001004573

CPTAC Proteogenomic Study

Recently, significant progress has been made in characterizing and sequencing the genomic alterations in statistically robust numbers of samples from several types of cancer. For example, The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC) and other similar efforts are identifying genomic alterations associated with specific cancers (e.g., copy number aberrations, rearrangements, point mutations, epigenomic changes, etc.) The availability of these multi-dimensional data to the scientific community sets the stage for the development of new molecularly targeted cancer interventions. Understanding the comprehensive functional changes in cancer proteomes arising from genomic alterations and other factors is the next logical step in the development of high-value candidate protein biomarkers. Hence, proteomics can greatly advance the understanding of molecular mechanisms of disease pathology via the analysis of changes in protein expression, their modifications and variations, as well as protein=protein interaction, signaling pathways and networks responsible for cellular functions such as apoptosis and oncogenesis. Realizing this great potential, the NCI launched the third phase of the CPTC initiative in September 2016. As the Clinical Proteomic Tumor Analysis Consortium, CPTAC continues to define cancer proteomes on genomically-characterized biospecimens. The purpose of this integrative approach was to provide the broad scientific community with knowledge that links genotype to proteotype and ultimately phenotype. In this third phase of CPTAC, the program aims to expand on CPTAC II and genomically and proteomically characterize over 2000 samples from 10 cancer types (Lung Adenocarcinoma, Pancreatic Ductal Adenocarcinoma, Glioblastoma Multiforme, Acute Myeloid Leukemia, Clear cell renal Carcinoma, Head and Neck Squamous Cell Carcinoma, Cutaneous Melanoma, Sarcoma, Lung Squamous Cell Carcinoma, Uterine Corpus Endometrial Carcinoma) .Germline DNA is obtained from blood and Normal control samples for proteomics varied by organ site. All cancer samples were derived from primary and untreated tumor.

Study phs001287

Molecular and clinical diversity in primary central nervous system lymphoma: a LOC Network study

Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood. We performed a comprehensive genome-wide analysis of 147 PCNSL from fresh-frozen tumor tissue from immunocompetent, treatment naïve PCNSL patients, employing whole-exome sequencing, assessment of somatic copy number alterations and DNA methylation, and RNA expression. These data were integrated and correlated with the clinico-radiological characteristics and outcomes of the patients. We validated our results in an independent series of 93 PCNSL formalin-fixed, paraffin-embedded (FFPE) samples. Consensus clustering of multi-omics data identified four robust, non-overlapping, prognostically significant clusters (CS) within PCNSL. The CS1 group, characterized by high proliferation and Polycomb Repressive Complex 2 (PRC2) complex activity had an intermediate outcome between CS2/CS3 and CS4. Patients who had PCNSL with an “immune-hot” (CS4) profile had the most favorable clinical outcome. In contrast, patients with the immune-cold hypermethylated CS2 and the heterogenous-immune CS3 groups had a poor prognosis. Nearly all PCNSL patients with meningeal infiltration harbored HIST1H1E mutations, enriched in the CS3 group. The integrated analysis suggests that the CS4 group may be more susceptible to immunotherapy. The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that significantly improved the current clinical stratification. This molecular classification using FFPE samples facilitates routine use in clinical practice and provides potential precision-medicine strategies in PCNSL.

Study EGAS00001006191

The light chain IgLV3-21 defines a new poor prognostic subgroup in Chronic Lymphocytic Leukemia: results from a multicenter study

Purpose: Unmutated (UM) immunoglobulin heavy chain region (IgHV) status or IgHV3-21 gene usage is associated with poor prognosis in chronic lymphocytic leukemia (CLL). Interestingly, IgHV3-21 is often co-expressed with light chain IgLV3-21 which is potentially able to trigger cell-autonomous BCR-mediated signaling. However this light chain has never been characterized independently of the heavy chain IgHV3-21.Experimental Design: we performed total RNA sequencing to characterize IgLV3-21 patients (n=32) and investigated IgLV3-21 prognostic impact in terms of treatment-free (TFS) and overall (OS) survival in 3 other independent cohorts for a total of 813 patients where IgLV3-21 presence was tested by real-time PCR and confirmed by Sanger sequencing.Results: Using total RNA sequencing to characterize 32 patients with high-risk CLL, we found a high frequency (28%) of IgLV3-21 rearrangements. Gene set enrichment analysis revealed that these patients present higher expression of genes responsible for ribosome biogenesis and translation initiation (P<0.0001) and MYC target genes (P=0.0003). Patients with IgLV3-21 rearrangements displayed a significantly shorter TFS and OS (P<0.05), in particular in IgHV mutated patients. In each of the 3 independent validation cohorts (n=813), we showed that IgLV3-21 rearrangements -similar to UM IgHV status- conferred poor prognosis compared to mutated IgHV (P<0.0001). Importantly, we confirmed in multivariate analysis that this was independent of IgHV mutational status or subset #2 stereotyped receptor (P<0.0001). Conclusions: We therefore demonstrate for the first time that a light chain can impact on CLL prognosis and that IgLV3-21 light chain usage defines a new poor prognostic subgroup in CLL.

Study EGAS00001002894

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

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