15038 results for "cancer studies using rna-seq"

in 72.46 milliseconds.

• Genome and gene analysis of gastrointestinal cancer and elucidation of its clinicopathological significance

  Cancer develops through the accumulation of genetic and epigenetic aberrations. To identify sequential molecular alterations that occur during the development of hepatocellular carcinoma (HCC), we molecularly compared 52 early and 108 overt HCC samples by genome sequencing. Gene mutations in the p53/RB1 pathway, WNT pathway, MLLs, SWI/SNF complexes, and AKT/PI3K pathway were common in HCC. In the early phase of all entities, TERT was the most frequently upregulated gene owing to diverse mechanisms. Despite frequent somatic mutations in driver genes, including CTNNB1 and TP53, early HCC was a separate molecular entity from overt HCC as each had a distinct expression profile. Notably, WNT target genes were not activated in early HCC, regardless of CTNNB1 mutation status, because ?-catenin did not translocate into the nucleus due to the E-Cadherin/?-catenin complex at the membrane. Conversely, WNT targets were definitively upregulated in overt HCC with CTNNB1 mutation associated with downregulation of CDH1 and hypomethylation of CpG islands in the target genes. Similarly, cell cycle genes downstream of the p53/RB pathway were upregulated only in overt HCC with TP53 and/or RB1 gene mutations associated with chromosomal deletion of 4q and/or 16q. Differing from the expression profile, HCC was epigenetically distinguished into four subclasses: normal-like methylation, global-hypomethylation (favorable prognosis), stem-like methylation (poor prognosis), and CpG island methylation. These methylation statuses were globally maintained through HCC progression. Taken together, additional molecular events besides driver gene mutations cooperatively contribute to transcriptional activation of downstream targets as HCC progresses, according to the methylation status of the associated genes.

  Study JGAS000233

• Histone chaperone CHAF1A promotes proliferation and tumorigenicity in gastric cancer and impacts prognosis via context-depedent regulation of gene expression

  The histone chaperone CHAF1A is associated with some tumors, but its mechanisms in tumor biology remain elusive. Gastric cancer (GC) has significant heterogeneity among patients, and novel prognostic markers and therapeutic targets may improve its outcomes. The role of CHAF1A in GC is unknown. In this study, we demonstrated that CHAF1A was overexpressed in GC tissues accompanied by low expression of wild-type P53 and high expression of the proliferation marker MKI67. In vitro, CHAF1A knockdown inhibited cell proliferation, induced cell cycle arrest and promoted apoptosis, while CHAF1A overexpression had contrary effects. In vivo, CHAF1A knockdown inhibited tumorigenicity of GC cells. A microarray assay with CHAF1A inhibition and a PathScan signaling antibody array with CHAF1A overexpression showed that CHAF1A inhibited the P53 pathway, activated stress response and induced glycolytic metabolism. In 665 patients, the expression level of CHAF1A protein was an independent predictor for overall survival and disease-free survival in non-cardia GC and also had survival associations in patients with small or perineural invasion-negative tumors. Tumor mRNA analyses based on next-generation sequencing in patients indicated that CHAF1A promoted the Warburg effect by depressing oxidative phosphorylation and increasing glycolysis. Furthermore, the heterogeneous clinical significance of CHAF1A among patient subgroups was associated with its differential regulation of gene expression involved with glycolysis and cell proliferation and survival, indicating that the role of CHAF1A is depended on patient characteristics. These results reveal critical roles and clinical values for CHAF1A in GC. CHAF1A may have context-dependent effects in GC, which increases understandings for GC heterogeneity.

  Study EGAS00001003064

• Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

  Study EGAS00001003427

• Spiradenocarcinoma

  • Spiradenocarcinoma is a rare cutaneous sweat gland adnexal cancer with potential for aggressive behaviour. They are classified histologically into low- and high-grade tumours, with morphologically low-grade tumours thought to behave more favourably. However, limited information is available, with only 18 published cases. • We have collected morphologically low-grade spiroadenocarcinomas (one with a lung metastasis) and high-grade spiroadenocarcinomas, as well as some spiradenomas (benign lesions), cylindromas (another type of malignant cutaneous sweat gland adnexal tumour) and hybrid spiradenoma-cylindromas. • H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB has been performed. The tumours were solitary, measuring 0.8-7?cm (median: 2.7?cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumours were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumours. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. • Here we wish to exome sequence these cases to define the first genomic landscape for this malignancy.

  Study EGAS00001001799

• Functional Mapping of AKT Signaling and Biomarkers of Response From the FAIRLANE Trial of Neoadjuvant Ipatasertib Plus Paclitaxel for Triple-Negative Breast Cancer

  Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or immunohistochemistry-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial. Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery. Adding ipatasertib did not increase pathologic complete response rate and numerically improved overall response rate by magnetic resonance imaging (MRI). We used reverse-phase protein microarrays (RPPA) to examine the total level and/or phosphorylation states of over 100 proteins in various signaling or cell processes including PI3K/AKT and mTOR signaling. 125 baseline and 127 on-treatment samples were evaluable by RPPA, with 110 paired samples at both time points. Results: Tumors with genomic/protein alterations in PIK3CA/AKT1/PTEN were associated with higher levels of AKT phosphorylation. In addition, phosphorylated(p)AKT levels exhibited a significant association with enriched clinical benefit of ipatasertib, and identified patients who received benefit in the absence of PIK3CA/AKT1/PTEN alterations. Ipatasertib treatment led to a down-regulation of AKT/mTORC1 signaling, which was more pronounced among the tumors with PIK3CA/AKT1/PTEN alterations or among the responders to the treatment. Conclusions: We showed that the high baseline pAKT levels are associated with the alterations of PI3K/AKT pathway components and enriched benefit of ipatasertib in TNBC.

  Study EGAS00001005892

• Whole-exome sequencing of hepatocellular carcinoma biopsies

  All 122 HCC biopsies and 115 non-tumoral tissues from 114 patients were subjected to whole-exome sequencing. Whole-exome capture was performed using the SureSelectXT Clinical Research Exome (Agilent Technologies) or SureSelect Human All Exon V6+COSMIC (Agilent Technologies) platforms according to the manufacturer’s guidelines. Sequencing was performed on an Illumina HiSeq 2500 at the Genomics Facility Basel according to the manufacturer’s guidelines. Paired-end 101-bp reads were generated.

  Dataset EGAD00001008182

• University of North Carolina at Chapel Hill (UNC) Hepatocellular Carcinoma Study by Exome Sequencing (HCCSES)

  Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma. As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in hepatocellular carcinoma. We performed whole exome sequencing on 87 hepatocellular carcinomas and matched normal adjacent tissues to an average coverage of 59x. The overall mutation rate was roughly 2 mutations per Mb, with a median of 45 non-synonymous mutations that altered the amino acid sequence (range 2 to 381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%), CTNNB1 (10%), KEAP1 (8%), C16orf62 (8%), MLL4 (7%) and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine rich repeat containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of hepatocellular carcinoma.

  Study phs000627

• Efficacy and safety of entrectinib in patients with ROS1-positive advanced/metastatic non-small cell lung cancer (NSCLC) from the Blood First Assay Screening Trial (BFAST)

  BFAST is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations, identified by blood-based molecular testing. We present data from Cohort D (ROS1-positive). Patients ≥18 years old with stage IIIB/IV, ROS1-positive NSCLC detected by blood-based testing, received entrectinib 600 mg daily. At data cut-off (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint; the confirmed objective response rate (ORR) by investigator was 81.5% which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR: 73.4%, data cut-off May 2019, ≥12 months follow-up). The safety profile of entrectinib was consistent with prior reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing and support the clinical value of blood-based testing to inform clinical decision-making.

  Study EGAS50000000105

• IL-27 promotes tumour control by enhancing cytotoxic T cell function

  Cytotoxic CD8+ T lymphocytes (CTL) are essential for anti-tumour immunity but are frequently dysfunctional in established tumours. Here, we show that expression of a CTL signature is strongly associated with IL-27 expression in diverse human and murine tumours. In mice, IL-27 acts directly on tumour-specific CTL to promote their persistence and effector function in the tumor microenvironment. Moreover, treatment with inducible IL-27 overexpression or a half-life-extended IL-27 protein in vivo is well tolerated, induces regression of large established tumours, drives an enhanced cytotoxic program in anti-tumour CTL, and synergizes with PD-L1 blockade. In cancer patients treated with anti-PD-1 or anti-PD-L1 therapy, high expression of IL-27 is associated with improved clinical response. Finally, IL-27 increases cytotoxicity and limits terminal differentiation of human CD8+ T cells during chronic antigen exposure. Our data demonstrate that endogenous IL-27 is essential for anti-tumour immunity and that IL-27 receptor agonism can safely improve anti-tumor T cell responses alone or in combination with PD-L1 blockade.

  Study EGAS50000000694

• Shallow Whole Genome Sequencing of Patient Derived Xenografts

  Chemotherapy is the standard-of-care treatment for metastatic colorectal cancer (mCRC) and benefits some patients, but what distinguishes responders from non-responders is unclear. In this study, we leveraged a comprehensive collection of 27 molecularly annotated patient-derived xenografts to uncover functional predictors of response to 5-FU and irinotecan combination therapy (FOLFIRI) in mCRC. Genetic analyses revealed that treatment sensitivity was marked by genomic scars indicative of BRCAness, suggesting homologous recombination (HR) deficiency as a key determinant. Accordingly, we surveyed a manually curated panel of 44 genes with a documented role in HR for the potential presence of pathogenic mutations. We did not observe a specific enrichment of HR gene mutations based on response to FOLFIRI. This result, combined with the absence of widespread biallelic inactivation of the analyzed genes and the predominance of mutations categorized as variants of unknown significance, suggests that FOLFIRI sensitivity is not primarily governed by underlying mutations in HR genes responsible for mitigating the genotoxic effects of this therapeutic regimen.

  Study EGAS50000000191

• Distinct genomic profiles and clinical outcomes in constitutional mismatch repair deficiency-associated high-grade gliomas: insights into mutational signatures and clonal evolution

  Constitutional mismatch repair deficiency (CMMRD) is a rare cancer-predisposition syndrome, yet the mutational processes and clonal evolution of CMMRD-associated high-grade gliomas (HGGs) remain incompletely understood. In this study, mutational signatures and tumor evolution were analyzed in 25 CMMRD-associated HGGs. Germline biallelic mutations were most frequently identified in MSH6 (56.0%), followed by PMS2 (36.0%) and MLH1 (8.0%). Affected patients showed very early disease onset (mean 5.8 years) and poor clinical outcomes, with a mean progression-free survival of 16 months. Distinct genomic and clinical differences were observed between MSH6- and PMS2-associated tumors. MSH6-deficient HGGs were enriched for SBS6, whereas PMS2-deficient tumors showed predominance of SBS21, and these mutational signatures were correlated with prognosis. Clonal evolution analyses revealed early involvement of POLE/POLD1 mutations and persistence of the founding clone at recurrence. Overall, the study highlights the importance of mutational signatures and clonal evolution in shaping tumor behavior and clinical outcomes in CMMRD-associated HGGs.

  Study EGAS50000001506

• Clonal hematopoiesis is associated with adverse outcomes in patients with COVID-19

  Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the occurrence of an expanded proportion of mature blood cells derived from a mutant hematopoietic precursor without evidence of hematological malignancies. The principle behind this is that the somatic mutation confers a fitness advantage to the cell in which it arose. Different clinical consequences are linked with this expansion. Early evidence of an association with higher mortality risk was provided. This was not related to higher rates of cancer but was associated in particular with increased cardiovascular mortality. Mechanistically, inflammatory processes are not only related to the development of clonal hematopoiesis, but in turn it is also a driver of inflammation. Besides pulmonary symptoms, COVID-19 evokes complex extra-pulmonary manifestations driving the pathophysiology. Among them, both inflammatory and cardiac-associated mechanisms have been deciphered. With the aim of assessing the impact of clonal hematopoiesis on the pathophysiology of COVID-19, hospitalized patients with severe or critical course were evaluated for the presence of CHIP driver mutations and, more importantly, the association with the clinical picture.

  Study EGAS00001006218

• Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma

  Tumor recurrence is a leading cause of cancer mortality. Therapies for recurrent disease may fail, at least in part, because the genomic alterations driving the growth of recurrences are distinct from those in the initial tumor. To explore this hypothesis, we sequenced the exomes of 23 initial low-grade gliomas and recurrent tumors resected from the same patients. In 43% of cases, at least half of the mutations in the initial tumor were undetected at recurrence, including driver mutations inTP53, ATRX, SMARCA4, and BRAF; this suggests that recurrent tumors are often seeded by cells derived from the initial tumor at a very early stage of their evolution. Notably, tumors from 6 of 10 patients treated with the chemotherapeutic drug temozolomide (TMZ) followed an alternative evolutionary path to high-grade glioma. At recurrence, these tumors were hypermutated and harbored driver mutations in the RB (retinoblastoma) and Akt-mTOR (mammalian target of rapamycin) pathways that bore the signature of TMZ-induced mutagenesis.

  Study EGAS00001000579

• Genetic_mechanisms_of_resistance_to_chemotherapy_in_breast_cancer

  Resistance towards chemotherapy is one of the main causes of treatment failure and deathamong breast cancer patients.The main objective of this project is to identify genetic mechanisms causing some breastcancer patients not to respond to a particluar type of chemotherapy (epirubicin) while otherpatients respond very well to the same treatment.In the project we will perform genome / exome sequencing of a selection of breast cancerpatients (n=30). These patients are drawn from a cohort where all patients have recievedtreatment with epirubicin monotherapy before surgical removal of a locally advanced breasttumour, and where all patients have been subjected to objective evaluation of the response tothe therapy.Subsequent to sequencing, we will analyse the data and compare with the clinical data foreach patient (object response to therapy). The main aim being to identify mutations that areassociated with resistance to epirubicin.Identification of mutations with strong predictive value, may have a direct impact on cancertreatment since it opens the possibility for genetic testing of a tumour, and desicion on whichdrug is likely to work best, prior to treatment start.

  Study EGAS00001000276

• The ICGC-TCGA DREAM Somatic Mutation Calling - Tumour Heterogeneity Challenge

  Tumors are composed of many different cell types, ranging from the normal tissue micro-environment, infiltrating immune cells and tumour cells. This group of tumour cells is itself intrinsically highly heterogeneous, driven by the rapid mutation rate of cancer cells to become a mixture of different sub-populations. These different types of cells, called subclones, have different sets of mutations in their DNA. Because some subclones evolve from others, many subclones share mutations. While it is increasingly easy to determine what mutations are present in the tumor, it remains very difficult to determine which subclones have which mutations. The task of assigning mutations to subclones is called subclonal reconstruction.The ICGC-TCGA DREAM Somatic Mutation Calling - Tumour Heterogeneity Challenge (SMC-Het) is an international effort to improve standard methods for subclonal reconstruction: to quantify and genotype each individual cell population present within a tumor. The goal of this challenge is to identify the best subclonal reconstruction algorithms and to identify the conditions that affect their performance.

  Study EGAS00001002092

• WGS of T-cell and NK-cell lymphoma for ICGC (NKTL-SG)

  Lymphomas are malignancies originating from the lymphatic system and there is a worldwide significant increase in incidences of this cancer. Lymphomas can be further classified into 2 categories namely Hodgkin’s (HL), and Non-Hodgkin’s lymphoma (NHL). The latter can be divided further into B, T and NK cell NHL. Peripheral T-cell lymphoma (PTCL) and Natural Killer/ T-cell lymphoma (NKTL) arise from mature T lymphocytes and NK cells. The more common subtypes include NKTL, PTCL not-otherwise-specified (PTCL-NOS), systemic anaplastic large cell lymphoma (ALCL), follicular PTCL (F-PTCL), angioimmunoblastic T-cell lymphoma (AITL) and enteropathy-associated T-cell lymphoma (EATL). Whole genome analyses on T-cell and NK-cell lymphoma samples from various countries to gain a better understanding of the pathogenesis and biology of these tumors. The comprehensive profiling and comparison among patients from various countries with different etiopathogenesis will hopefully facilitate the elucidation of key pathways and underlying molecular mechanisms driving these cancers, opening up novel therapeutic strategies in the future.

  Study EGAS00001002398

• Somatic_mutation_profiling_of_intestinal_crypts_from_IBD

  In this project we want to investigate the role that somatic mutations in intestinal stem cells play in IBD. We will use laser capture microdissection to ascertain epithelial cells from an individual crypts/vilus. We will extract DNA from these and use a new low-input material library prep methods to make accurate libraries for sequencing. In this pilot phase of the project we will perform 15X whole-genome sequencing of a small number of crypts biopsied from four patients. Biopsies have been taken from inflammed and noninflammed patches to compare mutation rates and mutational signatures. We will also test if crypts from inflammed patches of a single patient are clonal (either within a given inflammed patch or across inflammed patches). We will quantify the rate of cancer driver mutations in inflammed and non-inflammed crypts. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001002896

• DERMATLAS__Porocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005720

• DERMATLAS__Porocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are porocarcinomas.

  Study EGAS00001005721

• DERMATLAS__Poroma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001005759

• Molecular origins of mpMRI visibility

  Multiparametric magnetic resonance imaging (mpMRI) has transformed the landscape of prostate cancer (PCa) management. Prostate Imaging Reporting and Data System (PI-RADSv2) scores reflect function and correlate phenotypic features with tumor aggressiveness, is an independent predictor of biochemical recurrence, and may distinguish low-risk tumors requiring no treatment from high-risk tumors requiring aggressive management. We hypothesize that differences in functional mpMRI of prostate tumors reflect the genetic and epigenetic heterogeneity of PCa. We profiled the genomes and transcriptomes of 40 Gleason score 3+4 tumors, of which 20 tumors were mpMRI invisible (not PI-RADSv2 3-5) and 20 tumors were visible (PI-RADSv2 5). Genomes of visible tumors were more unstable than those of invisible tumors. We identified 62 enriched transcripts, including numerous snoRNAs, Relaxin 1 and SCHLAP1, in visible tumors. These data suggest a confluence of aggressive pathological and microenvironmental phenomenon in PI-RADSv2 5 tumors reminiscent of nimbosus, while linking the molecular profiles of tumor aggressiveness with their functional features on mpMRI.

  Study EGAS00001003179

• Sensitive detection of tumor mutations from blood and its application to immunotherapy prognosis

  Cell-free DNA (cfDNA) is attractive for many applications, including cancer detection, locating, and monitoring. A fundamental task underlying these applications is the SNV calling from cfDNA, which, however, faces a new challenge, namely, the generally very low tumor content in cfDNA. Thus all existing callers fail to achieve satisfactory performance. Here we present cfSNV, a method incorporating multi-layer error suppression and hierarchical mutation calling, to address this important challenge. Furthermore, by leveraging cfDNA’s comprehensive coverage of clonal landscape, for the first time cfSNV can profile mutations even in subclones. In both simulated and real patient data, cfSNV vastly outperforms existing tools, showing tens of times increase in sensitivity in detecting mutations with low allele frequency while maintaining high precision. cfSNV can enhance the clinical utilities of cfDNA by dramatically reducing the required sequencing depth and therefore reduce the cost by magnitudes, and further make the Whole-Exome-Sequencing of cfDNA a viable option. As an example, we demonstrate that cfDNA-WES allows a new biomarker to effectively select patients for immunotherapy.

  Study EGAS00001004373

• DERMATLAS__Poroma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are poromas.

  Study EGAS00001007705

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_WES

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

  Study EGAS00001007745

• DERMATLAS__SG_basal_cell_adenoma_and_adenocarcinoma_RNAseq

  Virtually no other tumour type is associated with so many different forms as skin cancer. Histologically, tumours of the skin may arise from epithelium, including epidermis, hair follicle, sebaceous or sweat gland, melanocytes, dermal-associated mesenchymal structures or tissue resident immune cells, making for a diversity of clinical presentations. Importantly, many skin tumour types have an extremely poor prognosis. Many skin tumour subtypes have never undergone molecular profiling, or if they have, targeted sequencing has been used and the number of cases analyzed has been so limited that deriving firm conclusions about the profile of driver genes, DNA mutational signatures and germline alleles has not been possible For 70 key skin tumour subtypes defined by the World Health Organization, that have not undergone extensive genetic analysis previoulsy, we propose to perform whole exome and transcriptome sequencing, from a range of body sites, to build a genomic atlas of dermatological tumours, including detailed maps of SNVs, copy number alterations, genome-wide methylation and expression profiles. The cases in this cohort are SG basal cell adenomas and adenocarcinomas.

  Study EGAS00001007746

• cell-free DNA Whole Genome Sequencing of 3784 samples on MGI and Illumina platform

  The dataset of Integrative modeling of tumor genomes and epigenomes for enhanced cancer diagnosis by cell-free DNA includes 3784 whole genome sequencing bam files on the MGI and Illumina platform. The analyzed samples include plasma samples from normal individuals and patients with cancer.

  Dataset EGAD00001009335

• Whole-genome sequencing of gastric cancer 81 samples in the Japanese population.

  Genomic DNA of 81 cases from Japanese gastric cancer was extracted from tumor and matched normal tissues, and libraries with an insert size of 350–550 bp were prepared. The libraries were sequenced on a HiSeq 2500 instrument (Illumina) with paired-end reads of 101 bp. The read data are stored as FASTQ formatted files.

  Dataset EGAD00001008610

• early-stage ESCC sequencing study

  We performed a comprehensive multi-omics analysis of 786 trace-tumor-samples from 154 esophageal squamous cell carcinoma phase (ESCC) patients, covering 9 histopathological stages in 3 phases as nontumor phase (NT phase), intraepithelial neoplasia phase (IEN phase), and ESCC phase. Proteogenomics elucidated the stage-specific molecular characterization and defined the cancer-driving waves along with the mutation accumulation in EC progression. The integrated multi-omics uncovered the chromosome 3q gain was the key event in the transmit from the NT to IEN phase, disclosed the top mutation of TP53 enhanced cell cycle and DNA replication in the IEN phase, and revealed the ESCC phase mutations of AKAP9 and MCAF1 elevated glycolysis and Wnt signaling, respectively. Furthermore, the trajectory analysis identified 6 major tracks related to different clinical features during ESCC progression. Growingly enhanced and hyperphosphorylated phosphoglycerate kinase 1 (PGK1, S203) was detected and considered as a drug target in ESCC progression. Collectively, this study provides insight into the understanding of ESCC molecular mechanism and a valuable resource for the development of therapeutic targets.

  Study EGAS00001006126

• Pediatric Low-Grade Glioma RNA and Targeted Sequencing

  Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS/MAPK pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. 84% of cases harbored a driver alteration, while those without an identified alteration also often exhibited up-regulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared to SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.

  Study EGAS00001004242

• Correlative Genomic Analysis of Durvalumab plus Pazopanib Combination in Patients with Advanced Soft Tissue Sarcomas

  We conducted an open-label, phase 2 study to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 immune checkpoint inhibitor, durvalumab, in unselected advanced sarcomas. In addition, we conducted whole exome and transcriptomic sequencing with pre-treatment tissue biopsy to correlate clinical outcomes with molecular and genomic biomarkers to identify patients who would most likely benefit from the combination treatment.

  Study EGAS50000000082

• Stand Up 2 Cancer (SU2C) Genomics-Enabled Medicine for Melanoma (GEMM) Trial

  The goal of the GEMM Trial is to ascertain if comprehensive and systematic interrogation of a patient's tumor molecular profile improves outcomes compared to the current practice of physician's choice for metastatic melanoma patients who have progressed following first line therapy. The data shared here includes tumor/normal exome and tumor RNAseq data for the trial patients, as well as archival data for a subset of patients.

  Study phs001786

• Cergentis FFPE-TLC sequencing of colorectal carcinoma

  In this study, formalin-fixed paraffin-embedded targeted locus capture (FFPE-TLC) sequencing is used as a novel technology for targeted detection of tumor-specific genomic structural variants (SVs) in the primary tumor of 29 colorectal cancer patients with metastatic disease. The tumor region was macrodissected and sequenced for 29 patients, and the "normal" region of the same slide was macrodissected and sequenced for 8 of these patients. SVs were found in the common fragile site (CFS)-associated genes MACROD2, PRKN, FHIT and WWOX as well as SVs caused by three LINE transposable elements. Tumor-specificity of selected SVs was independently verified by droplet digital PCR of tumor tissue DNA and their applicability as plasma circulating tumor DNA biomarkers was demonstrated. This dataset contains the hg19 reference alignment of the FFPE-TLC sequences for all 29 colorectal cancers and 8 adjacent normals.

  Dataset EGAD50000000618