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• The Familial Intracranial Aneurysm Linkage Study (FIA)

  Our long-term objective is to identify susceptibility genes that are related to the formation of intracranial aneurysms (IA). Rupture of IAs occurs in 16,000 to 17,000 persons in the U.S. annually and nearly half of affected persons are dead within the first 30 days. An additional 6,000 to 7,000 persons with unruptured IAs are identified each year. Accumulated evidence indicates that a genetic component plays an important role in the development of IAs, but specific loci affecting the risk of IA have not been identified. The primary hypothesis of this study is that there are specific human chromosomal regions that are associated with an increased risk of IAs. Specific Aims of are: Recruitment of 400 (475) families with multiple individuals who have an IA through 23 (25) referral centers throughout North America, Australia, and New Zealand that represent 35 (40) recruitment sites. Ascertainment of interviews and blood samples from all affected family members as well as their first-degree relatives. White blood cells from living persons with an IA will be cryopreserved at Coriell Institute for Medical Research for future immortalization of cells lines as indicated. Identification of unruptured IAs by obtaining MRAs in selected asymptomatic siblings (of affected individuals). Completion of a 10 cM genome series in persons with IAs as well as the spouses and children of persons with an IA who are deceased. We will perform finer mapping of chromosomal regions with suggestive evidence of linkage in the genome screen. Performance of a nonparametric (allele sharing) linkage analysis, including relevant environmental factors such as smoking, to identify chromosomal regions linked to IA. Reconstruction of the genotypes of deceased affected family members will be performed. Identification of individuals who are genetically at high risk for the development of IAs would enable targeted and effective screening/prevention/treatment strategies to reduce the substantial mortality and morbidity associated with this devastating type of stroke. Only a multidisciplinary, collaborative effort to identify, accrue, and genotype FIA families will be successful in identifying sufficient high-risk families to characterize the genetic underpinnings of IA.

  Study phs000293

• PD-L1 blockade immunotherapy rewires cancer-induced emergency myelopoiesis

  Introduction Immune checkpoint blockade (ICB) immunotherapy has revolutionized cancer treatment, demonstrating exceptional clinical responses in a wide range of cancers. Despite the success, a significant proportion of patients still fail to respond, highlighting the existence of unappreciated mechanisms of immunotherapy resistance. Delineating such mechanisms is paramount to minimize immunotherapy failures and optimize the clinical benefit. Methods In this study, we treated tumour-bearing mice with PD-L1 blockage antibody (aPD-L1) immunotherapy, to investigate its effects on cancer-induced emergency myelopoiesis, focusing on bone marrow HSPCs. We examined the impact of aPD-L1 treatment on HSPC quiescence, proliferation, transcriptomic profile, and functionality. Results Herein, we reveal that aPD-L1 in tumour-bearing mice targets the hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (ΒΜ), mediating their exit from quiescence and promoting their proliferation. Notably, disruption of the PDL1/PD1 axis induces transcriptomic reprogramming in HSPCs, observed in both individuals with Hodgkin lymphoma (HL) and tumour-bearing mice, shifting towards an inflammatory state. Furthermore, HSPCs from aPDL1-treated mice demonstrated resistance to cancer-induced emergency myelopoiesis, evidenced by a lower generation of MDSCs compared to control-treated mice. Discussion: Our findings shed light on unrecognized mechanisms of action of ICB immunotherapy in cancer, which involves targeting of BM-driven HSPCs and reprogramming of cancer-induced emergency myelopoiesis.

  Study EGAS00001007873

• Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome

  This study aimed to assess the effectiveness of whole genome sequencing (WGS) compared to whole exome sequencing (WES) in identifying driver alterations in cancer genomes. Out of 177 cases with no driver alterations detected by WES, WGS identified driver alterations in 68.4% and likely driver alterations in 22.6% of cases. The most common alterations found were oncogene amplifications, tumor suppressor gene deletions, and small variants outside coding regions. WGS proved valuable in uncovering genomic changes associated with cancer development.

  Study JGAS000715

• CHEK2 molecular manuscript

  This study investigated the molecular landscape of 17 tumors from 9 individuals with biallelic germline pathogenic variants in CHEK2. Tumors included breast and non-breast cancers, and WES and sWGS bam files from the tumors are included in this submission. WES data was aligned to GRCh37 and sWGS data to GRCh38.

  Study EGAS50000000080

• Genomic characterization of metastatic breast cancers

  While large efforts have been done to characterize early breast cancer, little is known about the genomic landscape of metastatic breast cancer. In the present study, we performed whole exome sequencing of 629 metastatic breast cancers, in order to identify new candidate targets and better stratify patients eligible for innovative therapies.

  Study EGAS00001003290

• Genomic Origins and Admixture in Latinos (GOAL)

  The GOAL Study was designed to comprehensively evaluate the genomic architecture of diverse Hispanic/Latino individuals with origins from the Caribbean, Central and South America, and to understand the impact of this diversity on genetic disease studies. Population structure and admixture are key confounders in genome-wide association and medical resequencing studies. In particular, accounting for difference in ancestry among cases and controls, both in terms of genomic and geographic location, is critical for proper analysis and interpretation of studies with multi- and trans-ethnic samples. Genomic studies of Hispanics/Latinos, the largest and fastest growing minority group in the US, reveal that they are a highly genetically heterogeneous admixed group with immense variation among individuals and populations in the proportions of African, European, and Native American ancestry. Knowledge of the underlying complex genetic structure of US Hispanic/Latino and Caribbean populations is, therefore, essential to ensuring robustness of genotype-phenotype associations and understanding the medical relevance of associated variants across diverse populations in the US and throughout the Americas. Furthermore, since much is known about the African and European migrations into the Americas over the past 500 years, population genetic studies of Hispanics/Latinos serve as an excellent model for developing novel algorithms and approaches for characterizing fine-scale genetic structure of admixed populations, in general. This project extends current studies of population genetic structure in US Hispanics/Latinos by densely genotyping parent-offspring triads from individuals (sampled in the US) of Caribbean-descent from six Latin American countries: Puerto Rico, Cuba, Dominican Republic, Haiti, Honduras and Colombia. This study will provide immediate insights and new statistical methods to improve study design and genetic analysis for medical genomic studies in Hispanics/Latinos, other complex admixed groups, and multi- and trans-ethnic studies.

  Study phs000750

• Genomic Evolution of Low- and High-Grade Glioma

  Malignant transformation (MT) of IDH-mutant low-grade glioma (LGG) to aggressive high-grade tumors is an event of major clinical significance, eventually leading to death in the majority of LGG patients. While patients with primary glioblastoma (GBM) have benefited from increased overall survival due to treatment with the alkylating chemotherapy temozolomide (TMZ), the benefit of TMZ for patients with diffuse low-grade gliomas (LGG) remains unknown. To further explore the relationships among TMZ treatment, hypermutation and malignant progression, we studied tumor evolution in an expanded cohort of untreated and TMZ-treated patients by exome-sequencing of paired IDH1/2-mutant LGGs and their post-TMZ recurrences. Together, these findings further our understanding of the molecular features and clinical behavior of hypermutated clones. The heterogeneity present in individual tumors, i.e. intratumoral heterogeneity (ITH), is thought to be a major reason why targeted treatments eventually fail. However, we know little about ITH in most human tumors because studies typically analyze one biopsy per tumor without knowledge of where in the tumor the sample was taken. Understanding how malignant and non-malignant cellular populations are distributed in 3D tumor space is foundational knowledge for resolving how human tumors grow, with translational implications for identifying representative biopsy specimens and predicting the impact of targeted therapy. Diffuse gliomas are incurable brain tumors with variably aggressive molecular subtypes. To determine the extent of ITH and its 3D organization in diffuse glioma, we prospectively collected a median of 10 spatially mapped samples from newly diagnosed and recurrent patient tumors, including aggressive canonical IDH1/IDH2 wild-type (IDH-wtc) glioblastoma, slower-growing IDH1/IDH2 mutant (IDHmut) glioma and a noncanonical IDH-wt glioblastoma (IDH-wtnc) lacking the TERT promoter mutation typical of canonical Glioblastoma.

  Study phs002034

• Whole-Genome and Exome Sequencing in clear-cell Renal Cell Carcinoma (ccRCC)

  Study to evaluate the molecular genetics of ccRCC through integrative analyses of tumors and tumorgrafts using multiple platforms in clinically annotated samples. Genome and exome data for patients giving consent to have the information available on a public, secure, database is being submitted.

  Study phs000491

• Study to investigate the prevalence of leukaemic mutations in whole blood DNA in a cohort of blood donors

  The aim of this study is to ascertain whether leukaemic mutations exist within the blood of people with otherwise normal haematopoeisis. To satisfy this aim we plan to look for 7 known leukaemic mutations in the whole blood DNA of a large cohort of blood donors who have normal haematopoesis. Genomic regions around mutational sites have been amplified using a 2 step PCR process which involves barcoding of individual patients

  Dataset EGAD00001001319

• Common Fund (CF) Genotype-Tissue Expression Project (GTEx)

  Lay Description The aim of the Genotype-Tissue Expression (GTEx) Project is to increase our understanding of how changes in our genes affect human health and disease with the ultimate goal of improving health care for future generations. GTEx will create a database that researchers can use to study how inherited changes in genes lead to common diseases. GTEx researchers are studying genes in different tissues obtained from many different people. The GTEx project also includes a study of the GTEx donor consent process - this study will help ensure that the consent process and other aspects of the project effectively address the concerns and expectations of participants in the study. GTEx is a pioneering project that uses state-of-the-art protocols for obtaining and storing a large range of organs and tissues, and for testing them in the lab. Until now, no project has analyzed genetic variation and expression in as many tissues from the same person in such a large population as planned for GTEx. Scientific Description Understanding the role of variation in the human genome is crucial to elucidating genetic contributions to human health and disease. Despite the results of genome-wide association studies (GWAS) documenting strong statistical associations between genetic variation and human traits, the functional role for most of these variants is largely unexplained. Nearly 90% of these GWAS-implicated sites lie outside of protein-coding sequences, suggesting that these variants might regulate gene expression. The goal of the Genotype-Tissue Expression (GTEx) project is to establish a resource database and tissue biobank in which to study the relationship between genetic variation and gene expression and other molecular phenotypes in reference/non-diseased tissues. The ultimate resource will include approximately 960 post-mortem donors with several dozen tissues from each, a resource large enough to study both cis- and trans- gene expression quantitative trait loci (eQTLs). Some tissue will also be banked for additional molecular analyses. To request biosamples, please see the Biobank page for more information. GTEx was initially funded as a 2-year pilot project by the NIH Common Fund (CF) in 2010, and has been scaled up after demonstration of feasibility. The project will collect and analyze RNA levels in many different human tissues and each donor will be characterized for germline genetic variation through dense genotyping arrays and sequencing of either whole exomes or whole genomes. By treating RNA expression levels as quantitative traits, eQTLs will be identified as sites containing genetic variation that correlate with changes in RNA expression. Such eQTLs have been associated with 4%-12% of expressed human genes, and with common complex human diseases, including obesity, atherosclerosis, type 2 diabetes, Crohn's disease, and asthma. Additionally, few studies have examined the tissue specificity of eQTLs. A subset of banked tissue samples will also be analyzed for other molecular phenotypes, such as DNA methylation, DNaseI hypersensitivity sites, and proteomics. The GTEx project will thus serve as a resource database and tissue bank for many future studies, especially for understanding the functional basis of inherited susceptibility to disease. All GTEx releases since Version 5 follow the NIH Genomic Data Sharing (GDS) Policy whereby there are no restrictions on use or publication after release. Additional information about the GTEx Data Release and Publication policy can be found on the GTEx Data Portal at www.gtexportal.org.

  Study phs000424

• Genetic control of the transcriptomic response of monocytes to bacterial and viral stimuli assessed by RNA-seq in Africans and Europeans

  Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses, and their genetic and evolutionary determinants, remain undefined. Here, we characterized, using RNA-sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli - ligands activating Toll-like receptors pathways (TLR1/2, TLR4 and TLR7/8) and influenza virus - and mapped expression quantitative trait loci (eQTL). We identify multiple cis- and trans-eQTL that contribute to the marked differences in immune responses detected within and between populations, including a TLR1 master regulator that decreases expression of pro-inflammatory genes in Europeans only. We show that regulatory variants have been privileged targets of natural selection, uncovering evolutionarily advantageous mechanisms, such as attenuated inflammation. Finally, we demonstrate that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges, and identify archaic haplotypes that contributed to population genetic adaptation.

  Study EGAS00001001895

• Exome-seq, RNA-Seq, SNP array profiling of gastric tumor samples and cell lines.

  Gastric cancer is the second leading cause of worldwide cancer mortality, yet the underlying genomic alterations remain poorly understood. Here we performed exome and transcriptome sequencing and SNP array assays to characterize 51 primary gastric tumors and 32 cell lines. Meta-analysis of the exome data and previously published data sets revealed 24 significantly mutated genes in MSS tumors, and 16 in MSI tumors. More than half of the patients in our collection could potentially benefit from targeted therapies. We identified 55 splice-site mutations accompanied by aberrant splicing products, in addition to mutation-independent differential isoform usage in tumors. The ZAK kinase isoform TV1 is preferentially upregulated in gastric tumors and cell lines relative to normal samples. This pattern is also observed in colorectal, bladder, and breast cancers. Overexpression of this particular isoform activated multiple cancer-related transcription factor reporters, while depletion of ZAK in gastric cell lines inhibited proliferation. These results reveal the spectrum of genomic and transcriptomic alterations in gastric cancer, and identify isoform-specific oncogenic properties of ZAK.

  Study EGAS00001000736

• MRCA and MRCE SNP genotypes

  Gene expression levels can be an important link DNA between variation and phenotypic manifestations. Our previous map of global gene expression based on approximately 400K SNPs and 50K transcripts in 400 sib pairs from the MRCA family panel has been widely used to interpret the results of GWAS. Here, we more than double the size of our initial dataset with expression data on 550 additional individuals from the MRCE family panel using the Illumina whole genome expression array. We have used new statistical methods for dimension reduction to account for non-genetic effects in estimates of expression levels and we have also included SNPs imputed from the 1000 Genomes Project. Our methods reduced false discovery rates and increased the number of eQTLs mapped either locally or at a distance (i.e. in cis or trans) from 1,534 in the MRCA dataset to 4,452 (with <5% FDR). Imputation of 1000 Genomes SNPs further increased the number of eQTLs to 7,302. Using the same methods and imputed SNPs in the newly acquired MRCE dataset we identified eQTLs for 9000 genes. The combined results identify strong local and distant effects for transcripts from 14,177 genes. Our eQTL database (http://www.hsph.harvard.edu/faculty/liming-liang/software/eqtl/) based on these results is freely available to help define the function of disease-associated variants.

  Study EGAS00000000137

• Mapping_regulatory_variation_in_sensory_neurons_using_IPS_lines_from_the_HIPSCI_project

  Sensory neurons are nerve cells that are activated by sensory input such as heat, light and convey information to the brain. Although a key cell type in complex organisms, human sensory neurons are challenging to study because they are impossible to obtain from living donors. We have collaborated with the Neucentis Pharmaceutical Research Unit to differentiate sensory neuron like cells from human induced pluripotent stem cells derived as part of the Human Induced Pluripotent Stem Cells Initiative. We will sequence RNA from 100 IPS lines derived from healthy individuals and perform RNA-seq on the differentiated cells to identify noncoding variants that alter gene expression in human sensory neurons.

  Study EGAS00001001149

• The Somatic Mutational Landscape of Thyroid Cancer in Patients with Germline PTEN Mutations

  PTEN hamartoma tumor syndrome (PHTS) is associated with a high rate of thyroid cancer and benign thyroid disease, yet nothing is known of the genomic landscape of PHTS-associated thyroid tumors. In this study, exome sequencing was performed on 58 thyroid tumors (28 cancers, 30 benign nodules) from 19 patients with PHTS, sequenced in tumor-normal pairs. Somatic variant calling was utilized to determine the somatic mutational landscape of thyroid tumors in this population. This was then compared to the known mutational landscape of sporadic thyroid cancer in the general population using sequencing data from The Cancer Genome Atlas. The primary finding of the study was that PHTS-associated thyroid tumors had a unique genomic landscape, including a high frequency of second-hit somatic PTEN alterations compared to the sporadic thyroid tumors. Additionally, PHTS-associated thyroid cancers were found to have somatic alterations in BRAF, RAS family members, and genes associated with DNA double stranded break repair. Data available through dbGAP will include tumor BAM files for each tumor, normal BAM files for each patient, and MAF files for PHTS-associated thyroid cancer and PHTS associated benign thyroid nodules.

  Study phs003640

• bulk RNAseq analysis of tumor from 3 non-muscle-invasive bladder cancer patients

  We performed screenings of patient-specific neo-epitopes by tumor-infiltrating CD8+ T lymphocytes of 4 non-muscle invasive bladder cancer patients. After the tumor resection, these patients went on to receive BCG treatment as they had high-risk disease. In order to select the neo-epitopes, we performed bulk RNAseq of the bladder tumor to select the mutated genes that were expressed in the tumor (TPM >1). For patient UC2, 3 different tumors were resected at the same time and RNA from these 3 tumors were sent separately for RNAseq. For patient UC4, no RNA was available, so this patient is not included in this study.

  Study EGAS50000001383

• ICGC Oesophageal adenocarcinoma - pilot samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett's oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000559

• ICGC Oesophageal adenocarcinoma - Barrett's samples

  The oesophageal project will focus on adenocarcinoma which is increasing in incidence in the UK and other developed countries and has a very poor outcome. The primary aims of this project are to deeply sequence tumour and normal genomic DNA (including the precursor condition Barrett’s oesophagus when material is available) to provide a comprehensive catalogue of somatic mutations. This will be achieved through a UK-wide network of hospitals involved in a research collaboration called the OCCAMS consortium. The goal of this project is to use high quality clinical material with accurately annotated clinic-pathological, treatment and outcome data.

  Study EGAS00001000726

• Deep single-cell RNA sequencing data for 11138 T cells from tumour, adjacent normal tissue and peripheral blood of treatment-naive CRC patients. The DATA ACCESS AGREEMENT is provided at https://github.com/zhangyybio/single-T-cell-data-access. Applicants can request access to the data by directly downloading it or by sending an email to cancerpku@pku.edu.cn. The process that is used to approve an application includes verifying the institution, participants and research purposes of the application. In general this process will take about two weeks. In principal, any scientific research program complying with the laws and bioethic regulation policies of China will be approved.

  T cells are central players in cancer immunotherapy1, yet some of their fundamental properties such as development and migration within tumours remain elusive. The enormous T cell receptor (TCR) repertoire, required for recognising foreign and self-antigens2,3, could serve as lineage tags to track these T cells in tumours4. Here, we obtained transcriptomes of 11,138 single T cells from 12 colorectal cancer (CRC) patients and developed STARTRAC (Single T-cell Analysis by Rna-seq and Tcr TRACking) indices to quantitatively analyse dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. While both CD8+ effector and “exhausted” T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, the majority of tumour-infiltrating Tregs showed clonal exclusivity, whereas certain Treg clones were developmentally linked to multiple TH clones. Notably, we identified two IFNG+ TH1-like clusters in tumours, the GZMK+ TEM and CXCL13+ TH1-like clusters, which were associated with distinct IFN-γ-regulating transcription factors, EOMES/RUNX3 and BHLHE40, respectively. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in tumours of microsatellite-instable (MSI) patients, which might explain their favourable response rates to immune-checkpoint blockade. Furthermore, we found IGFLR1 to be highly expressed in both CXCL13+BHLHE40+ TH1-like and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provides a powerful avenue to comprehensively dissect the T cell properties in CRC, which could shed new insights into the dynamic relationships of T cells in other cancers

  Study EGAS00001002791

• Gene-Specific RNA Sequencing in PLCG2-Associated Immune Dysregulation with Cold Urticaria

  This study utilized gene-specific RNA-sequencing of PLCG2 to screen for disease causing in-frame exon-skipping transcripts of PLCG2 in a collection of 9 subjects with cold urticaria, 2 subjects with known PLCG2-associated antibody deficiency and immune dysregulation (PLAID)-causing deletions of PLCG2 (positive controls) and 3 healthy subjects (negative controls). Full length cDNA of PLCG2 was generated using gene specific reverse transcription of peripheral blood mononuclear cell RNA. The full length PLCG2 cDNA was used as the template to create Illumina sequencing libraries. To identify the underlying genetic basis for the exon-skipping transcripts, trio-based whole genome sequencing was performed for probands in whom in-frame exon-skipping transcripts of PLCG2 were identified.

  Study phs003807

• Exploiting New Patterns of Genome Damage in Triple Negative Breast Cancer

  Genomic instability, a feature of triple negative breast cancers (TNBC), represents an opportunity for discovery of biologic and clinically relevant subgroups of patients. Owing to TP53 mutation in the majority of cases, DNA repair deficiency through loss of BRCA1 and BRCA2, and by expression features patterning a basal cell of origin, TNBC represents a molecularly and clinically distinct group of breast cancer patients. Unfortunately, targetable molecular features of TNBC remain elusive and TNBC patients suffer the poorest outcomes amongst clinical subgroups. Within TNBC patients, responses to treatment vary and although gene expression patterns within TNBC have been identified, little progress has been made in developing biomarkers; effective stratification as a route to directing patients to more targeted therapy is lacking. In this study, we exploit mutational processes in TNBC as a new opportunity to stratify patients and to understand the evolutionary progression of TNBC cells harboring specific DNA repair properties.

  Study phs003038

• 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

• Basal-to-Inflammatory Transition Contributes to Basal Cell Carcinoma Therapy Resistance via Crosstalk with a Pro-Inflammatory Stromal Niche

  Overcoming tumor evolution and inducible resistance states remain the main challenge to creating successful anti-tumor therapies. The body's cancer-associated inflammatory response is a double-edged sword having ill-defined pro- and anti-tumor properties. Our group previously identified a basal cell carcinoma (BCC) tumor-intrinsic resistance pathway called basal to squamous cell carcinoma transition (BST). However, tumor resistance driven through the complex dynamics of tumor interactions with the inflammatory response remains poorly studied. Here, employing a multipronged approach combining human tumor single-cell transcriptomics, single-cell chromatin accessibility (scATAC-Seq) study, CODEX multiplexed imaging, spatial transcriptomic along with functional validation, we have identified a surprising inflammation-associated SMOi therapy enriched tumor epithelial cell state we term basal-to-inflammatory transition (BIT). Marked by CHI3L1, TAGLN, ITGAV, and VCAM1, BIT arises in spatially distinct neighborhoods from BST in a subset of naive BCCs. While BST tumor epithelium occurs within the central cores of tumor nodules, BIT tumor epithelium arises in a specialized inflammatory environment defined by a tumor associated TREM1 myeloid signature. IL1 and OSM secreted by TREM1 myeloid cells activate the inflammatory NF-kB family of transcription factors within the BIT tumor epithelium. Strikingly, IL1 and OSM ligands are sufficient not only in inducing the BIT tumor state in vitro and in vivo in a synergistic fashion but also in lowering the sensitivity of human BCC explant tumors to SMOi treatment. This work provides critical insights into the BIT-resistant state as a novel targetable tumor state driven by a specialized inflammatory microenvironment.

  Study phs003437

• Distinct evolutionary trajectories of primary high grade serous ovarian cancers revealed through spatial mutational profiling

  High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment-resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2 to 91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole-genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug-resistance mechanisms

  Dataset EGAD00001000669

• ATRX mutant neuroblastoma is sensitive to EZH2 inhibition via modulation of neuronal differentiation.

  Mutations and structural alterations of the SWI/SNF-like chromatin remodeler ATRX have been reported at high frequency in a number of adult and pediatric tumors1. However, the consequences of ATRX (Alpha Thalassemia/Mental Retardation, X-linked) mutations in cancer and their underlying epigenetic sensitivities remain ill defined. Particularly intriguing are the large N-terminal deletions of ATRX in neuroblastoma that generate in-frame fusion (IFF) proteins1–3 devoid of key chromatin interaction domains. Here we demonstrate that neuroblastoma cells harbouring ATRX IFFs have distinct gene expression programs compared to neuroblastoma cells that are wild type for ATRX. This is due in part to H3K27me3-mediated silencing of REST (RE1 Silencing Transcription Factor) target genes involved in neuronal differentiation. In turn, we find that ATRX IFF cells display exquisite sensitivity to EZH2 inhibition in both adherent and tumorsphere conditions, due in part to derepression of neurogenesis genes, including REST targets. Examination of the epigenomic landscape of a pediatric neuroblastoma tumor harboring an ATRX IFF revealed that H3K27me3 occupies a subset of REST target genes that are transcriptionally silenced, and are sensitive to EZH2 inhibition in our cell-based assays. Thus, our study greatly advances our understanding of indolent neuroblastoma and identifies EZH2 inhibition as a potential therapy for patients with ATRX mutant disease. Further, these studies may be applicable to other ATRX mutant pediatric malignancies, particularly those carrying similar structural alterations of ATRX.

  Study EGAS00001002507