12450 results for ""non-traditional+communal+storytelling+approach"+novel+segment+noted+in+critical+commentary"

in 19.76 milliseconds.

• The study on genomic profiling using clinical specimens (tissue, blood, etc.) form patients with lung and thymic tumors

  The objective is to generate a comprehensive immunogenomic profiling in thymoma using RNA sequencing and TCR repertoire analysis and to evaluate the potential of immunotherapy in thymoma from multiple perspectives.

  Study JGAS000552

• CIAO Clinical Trial

  Whole exome and RNA sequencing for samples from CIAO (Checkpoint Inhibitors Assessment in Oropharynx cancer) (NCT03144778) clinical trial testing neoadjuvant anti-PD-L1 durvalumab with or without the anti-CTLA-4 tremelimumab in oropharynx cancer

  Study EGAS50000001174

• Single Cell RNAseq of blood and tumor from renal cancer patients

  Single-cell RNASeq (scRNAseq) showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and high IL8 expression was associated with the downregulation of the antigen presentation machinery in myeloid cells.

  Study EGAS00001004230

• Genetic and expression landscape of Waldenstrom macroglobulinemia

  Exome analyses for the identification of somatic mutation in Waldenstrom macroglobulinemia by comparison of tumor and CD3+(germ line control) population in 16 patients. transcription profiling of a series of Waldenstrom macroglobulinemia samples

  Study EGAS00001003603

• ChIP-seq bulk

  This dataset gather ChIP-seq data produced by immunoprecipitating CTCF factor in own laboratory in MM.1S cell line in EtOH and Dex conditions. It also gather ChIP-seq dataset produced by external laboratory (Active Motif) for H3K27ac mark and GR transcription factor in same cell line and conditions ( MM.1S ETOH/Dex)

  Dataset EGAD00001011136

• Genome_wide_CRISPR_Cas9_screening_of_Human_Organoids

  In this study we will exploit the bacterial clustered regularly interspaced short palindromic repeats (CRISPR) system to perform a genome-wide single-guide RNA (sgRNA) library to screen for genes required for proliferation and survival in human organoids.

  Study EGAS00001001932

• Therapeutic Resistance to PI3K-alpha Inhibitors

  We have studied the tumor genomic evolution in a patient with metastatic breast cancer bearing an activating PIK3CA mutation. The patient was treated with the PI3Kα inhibitor BYL719 and achieved a lasting clinical response on BYL719, but eventually progressed to treatment and died shortly thereafter. A rapid autopsy was performed and a total of 14 metastatic lesions were collected for further analysis. In order to identify possible genetic determinants of acquired resistance to PI3Kα inhibition, we took a three-step approach. First, we examined both the primary tumor (before BYL719 treatment) and the new lung metastasis by whole genome sequencing (DNA from the spleen was used as a normal control). Then, we analyzed the primary tumor, lung metastasis, and the peri-aortic lesion that remained stable (responding) at the time of progression to BYL719 therapy by whole exome sequencing. Finally, to confirm and expand our findings, we sequenced the primary tumor and all the metastatic lesions to >500-fold coverage using a custom targeted deep-sequencing assay, MSK-IMPACT. Using this 3-step approach, we have demonstrated that patient’s lesion underwent parallel genetic evolution at multiple metastatic sites with different PTEN genomic alterations leading to a convergent PTEN- null phenotype resistant to PI3Kα inhibition. In order to expand our observations, we analyzed paired samples (pre-treatment and at progression) from six additional patients enrolled in the BYL719 trial. Acquired bi-allelic loss of PTEN was found in one additional patient treated with BYL719 whereas in two patients PIK3CA mutations present in the primary tumor were no longer detected at the time of progression. To functionally characterize our findings, inducible PTEN knockdown in sensitive cells resulted in resistance to BYL719, while simultaneous PI3K-p110β blockade reverted this resistance phenotype, both in cell lines and in PTEN-null xenografts derived from our patient. We conclude that parallel genetic evolution of separate sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI3Kα inhibition.

  Study EGAS00001000991

• Functional Significance of Prostate Cancer Risk-SNPs

  Prostate Cancer (PrCa), the most frequently diagnosed solid tumor in men in the U.S., results in ~192,000 new cases and ~27,000 deaths per year. Although the variation of PrCa incidence is likely to be the result of several factors, there is a large body of literature that strongly implicates a genetic etiology. Genome-wide association studies (GWAS) have emerged as the most widely used contemporary approach to identify genetic variants (in particular SNPs) that are associated with increased risk of human disease. For PrCa, at least five GWAS have now been performed yielding a substantial number of well-validated SNPs that are associated with an increased risk of PrCa, and that number continues to grow. A significant problem for many of the PrCa risk-SNPs identified so far, however, is that they do not lie within or near a known gene and they have no obvious functional properties. These findings suggest that many (if not most) of these risk-SNPs will be located in regulatory regions that control gene expression rather than in coding regions that may directly affect protein function. Therefore, in order to define the functional role of currently known risk-SNPs, the target genes must first be identified. A promising strategy to address this problem involves the use of expression quantitative trait loci (eQTL) analysis. Unfortunately, most of the publically available SNP-Transcript eQTL datasets utilize lymphoblastoid cells with only a handful using tissue from target organs. Although useful, these datasets alone are unlikely to be sufficient. Recent studies have demonstrated that gene expression and gene regulation occur in both a tissue-specific and tissue independent fashion and suggest that a complete repertoire of regulatory SNPs can only be uncovered in the context of cell type specificity. To date, such a tissue-specific dataset for normal prostate tissue does not exist. In this study, we have constructed a normal prostate tissue specific eQTL data set.

  Study phs000985

• Collaborative Cohort of Cohorts for COVID-19 Research (C4R): Framingham Heart Study (FHS)

  Cohort DescriptionIn 1948, the researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have returned to the study every two years for an examination consisting of a detailed medical history, physical examination, and laboratory tests, and in 1971, the study enrolled a second-generation cohort -- 5,124 of the original participants' adult children and their spouses -- to participate in similar examinations. The second examination of the Offspring cohort occurred eight years after the first examination, and subsequent examinations have occurred approximately every four years thereafter. In 1994, the need to establish a new study reflecting a more diverse community of Framingham was recognized, and the first Omni cohort of the Framingham Heart Study, consisting of 506 participants, was enrolled. In April 2002 4095 third generation of participants, the grandchildren of the original cohort, were added. In 2003, 103 spouses of the offspring Cohort (NOS), and a second group of 410 Omni participants were enrolled. Through 2019, the original cohort has completed a total of 32 exams, the Offspring cohort 9 exams, the OMNI1 cohort 4 exams, and GEN3, NOS and OMNI2 cohorts each have completed 3 exams. The FHS is a joint project of the National Heart, Lung and Blood Institute and Boston University.Data Being Submitted Wave 1 questionnaire data includes 3967 variables for up to 3112 FHS participants in C4R.Wave 2 questionnaire data includes 448 variables for up to 2337 FHS participants in C4R.Dried Blood Spot/Serosurvey data includes 7 variables for up to 2189 FHS participants in C4R.Derived data includes 43 variables for up to 3151 FHS participants in C4R.Phenotype data includes 113 variables for up to 3151 FHS participants in C4R.

  Study phs002911

• Exploration of CNV’s and SNV’s in cancers with well-known genetic rearrangements: Identification of additional genetic changes in rearrangements-driven cancer

  Specific cancers are well known to have specific gene rearrangements. Representative cancer is chronic myeloid leukemia (CML) which is famous for BCR/ABL gene rearrangements. By the way, also genetic rearrangements are not infrequently found in acute leukemia, and those include CBFB/MYH11 rearrangements, PML/RARA rearrangements, AML/ETO rearrangements, and BCR/ABL rearrangements. The situation is same is for lung adenocarcinoma of non-smokers and prostate cancers, and ALK and RET gene rearrangements are recently found. However, not all these rearrangements are sufficient to develop cancer, and it is suggested that some genetic aberrations are required for the development and progression of cancer in addition to these genetic rearrangements. In this study, we have a plan to explore the existence of additional genetic changes including single nucleotide variants (SNV’s) and copy number variations (CNV’s) in cancers with specific genetic rearrangements so as to define additional genetic changes that confer full oncogenic potential to cancer cells. So as to look at SNV’s and small indels, we are going to use whole exome sequencing (WES) data. And as for CNV’s, we are going to use array-CGH data. Also, to check the functionality of these genetic changes, we are going to use whole transcriptome data (WTS). In addition, in samples with whole genome sequencing (WGS ) data, we are going to explore genetic changes in intronic regions also. In fact, we sequenced 10 AML samples which are known to have specific genetic rearrangements. Analysis of these WGS, WES and WTS data are under the way. If we have a chance to access WES, array-CGH and WTS data of other cancer samples with specific genetic rearrangements, we would be able to compare additional genetic changes required for oncogenesis in cancer cells with various genetic rearrangements. We hope this result will enlighten our understanding of cancer genetics further.

  Study EGAS00001000673

• Molecular Tumor Board to Inform on Personalized Medicine for a Man with Advanced Prostate Cancer

  Purpose: Molecular profiling of cancer is increasingly common as part of routine care in oncology, and germline and somatic profiling may provide insights and actionable targets for men with metastatic prostate cancer. However, all reported cases are of deidentified individuals without full medical and genomic data available in the public domain. Patient and Methods: We present a case of whole genome tumor and germline sequencing in a patient with advanced prostate cancer, who has agreed to make his genomic and clinical data publicly available in an accompanying personal testimonial. Results: We describe an 84-year-old Caucasian male with a Gleason 10 oligometastastic hormone-sensitive prostate cancer. Whole-genome sequencing provided insights into his tumor’s underlying mutational processes and the development of an SPOP mutation. It also revealed an androgen-receptor dependency of his cancer which was reflected in his durable response to radiation and hormonal therapy. Potentially actionable genomic lesions in the tumor were identified through a personalized medicine approach for potential future therapy, but at the moment, he remains in remission, illustrating the hormonal sensitivity of his SPOP-driven prostate cancer. We also placed this patient in the context of a large prostate-cancer cohort from the PCAWG (Pan-cancer Analysis of Whole Genomes) group. In this comparison, the patient's cancer appears typical in terms of the number and type of somatic mutations, but it has a somewhat larger contribution from the mutational process associated with aging. Conclusion: We combined the expertise of medical oncology and genomics approaches to develop a molecular tumor board to integrate the care and study of this patient, who continues to have an outstanding response to his combined modality treatment. This identifiable case potentially helps overcome barriers to clinical and genomic data sharing.

  Study EGAS00001004648

• WES_of_adult_intellectual_disabilities_with_co_morbid_psychiatric_disorders

  ost adults with intellectual disabilities (ID) do not undergo genetic diagnostic investigation as part of their clinical care and have 'missed the boat' with regard to the WES and WGS genetic testing that is now being provided for children with ID. There is a dramatically increased risk of psychistric disorders in adults with ID, e.g. the risk of psychoses is 10X higher than in the general population. It remains an open question as to how much of adult ID is genetic in origin and how similar the genetic forms of adult ID are to those being diagnosed in children, in part due to survivor bias. There is also the opportunity to identify adults with treatable forms of ID, of which over 80 have been described, thus improving their clinical management. Furthermore, analysis of medical records of adults with genetic forms of ID can help to characterise the 'natural history' of individual disorders, resulting in more accurate prognoses for diagnosed children and identifying opportunities for improved management and possibly therapeutic intervention (e.g. optimal anti-epileptic therapy). Here we propose to exome sequence (to ~50X coverage) 200 adults with ID and co-morbid psychiatric disorders. This cohort has previously been assayed with chromosomal microarrays (Wolfe et al 2017 EJHG, 25, 66–72) identifying a diagnostic yield of ~11% which is comparable to the CNV diagnostic yield in various child ID cohorts (10-15%). The authors observed no substantive biases in diagnostic yield between different psychiatric diagnostic classes. The WES data will be analysed using the diagnostic workflows developed in the DDD study to ensure comparability between child and adult ID datasets. This study is intended as a pilot study to demonstrate the value of WES in adults with ID. 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 EGAS00001002962

• The University of Hong Kong Colon Cancer GCV Study

  Background: Ganciclovir (GCV) is widely used in solid organ and hematopoietic stem cell transplant patients for prophylaxis and treatment of cytomegalovirus. It has long been considered a mutagen and carcinogen. However, the contribution of GCV to cancer incidence and other factors that influence its mutagenicity remains unknown. Methods: This retrospective cohort study analysed genomics data for 121,771 patients who had undergone targeted sequencing compiled by the Genomics Evidence Neoplasia Information Exchange (GENIE) or Foundation Medicine (FM). A statistical approach was developed to identify patients with GCV-associated mutational signature (GCVsig) from targeted sequenced data of tumour samples. Cell line exposure models were further used to quantify mutation burden and DNA damage caused by GCV and other antiviral and immunosuppressive drugs. Results: Mutational profiles from 22 of 121,771 patient samples in the GENIE and FM cohorts showed evidence of GCVsig. A diverse range of cancers was represented. All patients with detailed clinical history available had previously undergone solid organ transplantation and received GCV and mycophenolate treatment. RAS hotspot mutations associated with GCVsig¬¬ were present in 9 of the 22 samples, with all samples harbouring multiple GCV-associated protein-altering mutations in cancer driver genes. In vitro testing in cell lines showed that elevated DNA damage response and GCV¬sig are uniquely associated with GCV but not acyclovir, a structurally similar antiviral. Combination treatment of GCV with the immunosuppressant, mycophenolate mofetil (MMF), increased the misincorporation of GCV in genomic DNA and mutations attributed to GCVsig in cell lines and organoids. Conclusions: In summary, GCV can cause a diverse range of cancers. Its mutagenicity may be potentiated by other therapies, such as mycophenolate, commonly co-prescribed with GCV for post-transplant patients. Further investigation of the optimal use of these drugs could help reduce GCV-associated mutagenesis in post-transplant patients.

  Study EGAS00001006707

• Clinical Sequencing Exploratory Research Consortium: Incorporation of Genomic Sequencing into Pediatric Cancer Care

  This project includes data derived from subjects enrolled in the BASIC3 (Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care) study. BASIC3 is a National Genome Human Research Institute (NHGRI) and National Cancer Institute-funded Clinical Sequencing Exploratory Research (CSER) consortium project that focused on prospective implementation of clinical whole exome sequencing in the pediatric oncology clinic. The primary study objective were to integrate information from CLIA-certified germline and tumor exome sequencing into the care of newly diagnosed solid tumor patients at Texas Children's Cancer Center, and to perform parallel evaluation of the impact of tumor and germline exomes on families and physicians. Blood and frozen tumor (if available) samples were collected from children undergoing surgery or biopsy of newly diagnosed solid tumors and subjected to exome sequencing in a CLIA-certified laboratory. Germline and tumor (if applicable) exome sequencing reports were generated and submitted into the electronic health record and returned to each patient/family by their primary oncologist. In addition to the clinical exome sequencing, specific (optional) consent was requested for research sequencing studies. If this consent was obtained then research studies of some of the children and parents participating in the BASIC3 study (including tumor transcriptome and whole genome sequencing of blood and/or tumor) are performed. The Clinical Sequencing Exploratory Research Consortium Cohort is utilized in the following dbGaP sub-study. To view molecular data, and derived variables collected in this sub-study, please click on the following sub-studies below or in the "Sub-study" section of this top-level study page phs001383 Clinical Sequencing Exploratory Research Consortium Cohort. phs001026 BASIC3 phs001878 GMKF BASIC3

  Study phs001683

• Mechanisms of Risk for Sulfonamide Hypersensitivity

  Hypersensitivity (HS) reactions to sulfonamide antibiotics occur uncommonly, but with potentially severe clinical manifestations. A familial predisposition to sulfonamide HS is suspected, but robust predictive genetic risk factors have yet to be identified. Strongly linked genetic polymorphisms have been used clinically as screening tests for other HS reactions prior to administration of high-risk drugs. The purpose of this study was to evaluate for genetic risk of sulfonamide HS in the immunocompetent population using genome-wide association. Ninety-one patients with symptoms after trimethoprim-sulfamethoxazole (TMP-SMX) attributable to "probable" drug HS based on medical record review and the Naranjo Adverse Drug Reaction Probability Scale, and 184 age- and sex-matched patients who tolerated a therapeutic course of TMP-SMX, were included in a genome-wide association study using both common and rare variant techniques. Additionally, two subgroups of HS patients with a more refined clinical phenotype (fever and rash; or fever, rash and eosinophilia) were evaluated separately. For the full dataset, no single nucleotide polymorphisms were suggestive of or reached genome-wide significance in the common variant analysis, nor was any genetic locus significant in the rare variant analysis. A single, possible gene locus association (COL12A1) was identified in the rare variant analysis for patients with both fever and rash, but the sample size was very small in this subgroup (n=16), and this may be a false positive finding. No other significant associations were found for the subgroups. No convincing genetic risk factors for sulfonamide HS were identified in this population. These negative findings may be due to challenges in accurately confirming the phenotype in exanthematous drug eruptions, or to unidentified gene-environment interactions influencing sulfonamide HS. Reprinted under PLOS ONE's open access license, CC-BY (http://www.plos.org/open-access).

  Study phs001124

• Genomic Profiling of Pediatric B-cell Acute Lymphoblastic Leukemia

  Pediatric leukemia is the most common type of childhood cancer and, despite tremendous progress in treatment, remains the second leading cause of cancer deaths in children. B-cell acute lymphoblastic leukemia (B-ALL) is the most common type of pediatric leukemia. Recent studies using transcriptional profiling of large cohorts of pediatric B-ALL have shown that patients can be grouped into transcriptional subtypes that are often defined by specific driver mutations. Interestingly, many of these mutational subtypes are defined by gene fusions or rearrangements that drive altered expression of transcription factors (ETV6-RUNX1, PAX5, DUX4, TCF3-PBX1, ZNF384) or in chromatin regulatory machinery (KMT2A), suggesting that transcriptional dysregulation is a major driver of B-ALL. While the transcriptional distinctions are clear, the relationship between patients in terms of their chromatin regulatory landscape remains unclear. To address this, we profiled gene expression, open chromatin, and 3D genome folding in patient derived B-ALL samples. We identified that at the level of 3D genome organization, many chromatin interactions and looping events are shared across mutational subtypes, suggesting that shared transcriptional programs, in addition to group specific driver mutations, possibly regulate the chromatin landscape in B-ALL. Using RNA-seq and ATAC-seq data, we were able to identify "latent" signatures of expression related to non-mutant transcription factors (TFs) that also contribute to expression heterogeneity across TF subtypes. These are related to patient specific patterns of 3D genome folding, and in some cases, are predictive of disease outcomes. This study helps shed light on the chromatin landscape in B-ALL and furthers our understanding of the interactions between diverse mutant TFs that drive B-ALL and non-mutant TFs that help shape the B-ALL chromatin landscape.

  Study phs003226

• Puerto Rico Heart Health Program (PRHHP-BioLINCC)

  Data Access NOTE: Please refer to the “Authorized Access” section below for information about how access to the data from this accession differs from many other dbGaP accessions. Objectives: To investigate morbidity and mortality from Coronary Heart Disease (CHD) in Puerto Rican rural and urban men. The objectives of the study were: (1) to identify factors related to the development of CHD, (2) compare the etiology of disease in rural versus urban men, and (3) determine the prevalence and incidence of CHD and other cardiovascular diseases in Puerto Rican males.Background: As Puerto Rico became more industrialized in the 1940s and 1950s, mortality rates for CHD increased. Since many factors related to CHD can be relatively homogenous within a population, two contrasting subgroups were selected for study in Puerto Rico: a rural population of men from a mountainous community and an urban population selected from San Juan. The NHLBI initiated the Puerto Rico Heart Health Program in May, 1965 as a prospective study of lifestyle, environmental and biological factors in the progression of cardiovascular disease in Puerto Rican men.Participants: A total of 9,824 (2,976 rural, 6,848 urban) men, age 45 to 64 were examined at the baseline exam.Design: The examination consisted of standardized questionnaires to determine education, occupation, smoking habits, and physical activity. Trained interviewers conducted a nutritional survey through a 24 hour diet recall. Subjects were also examined to determine prevalent cardiovascular, cerebrovascular and peripheral vascular abnormalities. The examination included vital capacity, a 12-lead ECG, and laboratory tests for hematocrit, glucose, serum cholesterol, serum glycercides and lipoprotein electrophoresis. A medical history was also obtained. Three additional exams, approximately three years apart, were conducted and morbidity and mortality follow-up concluded in 1980.

  Study phs003930

• Molecular evolution of metastatic clear cell renal cell carcinoma progressing under tyrosine kinase inhibitor therapy (HIPO-045)

  Background:Acquired resistance to targeted drugs is largely due to intra-tumor molecular heterogeneity and clonal selection. Objective:The objective of this study was to determine molecular alterations and mediating resistant mechanisms and to suggest additional treatment options.Design, Setting, and Participants:Four patients were enrolled into the MORE (Molecular Renal Cancer Evolution) trial. We investigated the mutational spectra of metastatic clear cell renal cell carcinoma (ccRCC) at baseline and compared them to those upon clonal evolution at progression on systemic therapy with tyrosine kinase inhibitors.Outcome Measurements:DNA was isolated from tumor tissues after surgery, metastasis biopsies after progression on sunitinib or axitinib, and subjected to whole-exome sequencing (WES). In addition, the exomes of circulating tumor DNA (ctDNA) from two patients were sequenced at baseline and at progression.Results and Limitations:Our data provide evidence for clonal evolution and various acquired resistance mechanisms of ccRCC with subclonal mutations in FLT4, MTOR, ITGA3/5, SETD2, and VHL on metastatic progression. The limited number of shared mutations in tissue and plasma biopsies indicates that both sources provide complementary information, possibly due to mutations present in metastatic lesions which were not amenable to tissue sampling but are represented in the ctDNA. Conclusion:Acquired resistance to targeted therapies in metastatic ccRCC is due to intra-tumor heterogeneity and clonal evolution. Larger patient cohorts have to be studied to estimate the benefit of WES from biopsies and ctDNA for therapy decision in metastatic ccRCC.Patient Summary:We analyzed the molecular profiles of ccRCC patients in primary tissues and metastatic tissues upon progression on tyrosine kinase inhibitor therapy. Clinically relevant mutations upon progression were detected in the metastatic sites of all of four patients, suggesting that it might be possible to derive therapies based on sequencing the metastases.?HIPO-045

  Study EGAS00001001861

• Molecular_diagnosis_of_albinism

  Albinism is genetically heterogeneous rare genetic condition affecting 1:17000 in the Western world (but more frequent in Africa) whose main feature is a profound visual impairment, characterised by foveal hypoplasia, abnormal chiasmatic connections, nystagmus and photofobia. All these features result in severly altered visual acuity (<0,1), absent depth perception and poor night vision. People with albinism are primarily visually handicapped. In addition, for some types of albinism, the visual phenotype can be presented with partial or total hypopigmentation, hence resulting in a secondary phenotype which can lead to skin cancer if skin is not adequately protected. Recently a new syndrome has been described, FHONDA, with the same visual abnormalities of albinism but without pigment alteration. The traditional classification differentiates Oculoculatenous albinism (OCA), where hypopigmentation involves hair, skin and eyes versus Ocular Albinism (OA), where hypopigmentation only affects the eyes. These are non-sydrimic types of albinism. Some syndromic forms (Hermansky-Pudlak=HPS, Chediak-Higashi=CHS) affect cells beyond pigment cells, present in the lungs, immune system, platelets and intestines, resulting in more severe phenotypes that can be fatal. Mutations in at least 19 genes are assocaited with the corresponding types of albinism. Most hospitals will only diagnose the most frequent cases using traditional Sanger, MLPA approaches. Some will use CGH arrays. We aim to diagnose all cases of albinism through the Albinochip proposal, which combines a Sequenom first step of known mutations combined with subsequent NGS approaches. In some cases we fail to find a second mutation, these are good candidates for further full exome analyses. 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 EGAS00001002068

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - WXS

  B-PLL is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003275

• Genetic characterization of B-cell prolymphocytic leukemia: a hierarchical prognostic model involving MYC and TP53 abnormalities - RNA-seq

  B-cell prolymphocytic leukemia (B-PLL) is a rare disease, whose molecular pathology is largely unknown. We report here the cytogenetic and molecular findings in a large series of 34 B-PLL. Karyotype (K) was complex (≥3 abnormalities) in 73%, and highly complex (HCK≥5) in 45%. The most frequent chromosomal aberrations were: translocation targeting the MYC gene [t(MYC)] (62%), 17p deletion including TP53 gene (38%), trisomy 18/18q (30%), 13q14 deletion (29%), trisomy 3 (24%), trisomy 12 (24%) and 8p deletion (23%). Whole-Exome Sequencing performed in 16 patients revealed recurrent mutations in TP53 (6/16, 38%), MYD88 (n=4), BCOR (n=4), MYC (n=3), SF3B1 (n=3), FAT1 (n=3), SETD2 (n=2), CHD2 (n=2), CXCR4 (n=2) and BCLAF1 (n=2). The main group of patients (21/34, 62%) had a t(MYC) associated with a higher percentage of prolymphocytes (p=0.03), CD38 expression (p<0.001), lower K complexity (p=0.0004), mutations in MYC and in genes involved in RNA metabolism and chromatin remodeling. Principal component analysis of gene expression data showed that patients with t(MYC) clustered together. A second group with MYC gain (5/34, 15%), was associated with HCK≥5 (p=0,01) and trisomy 3 (p=0,008). Altogether, 26/34 patients (76%) had a MYC activation, translocation or gain, that were mutually exclusive. We identified 3 distinct cytogenetic prognostic groups (p=0.0006): lower risk: absence of MYC activation (median not reached); intermediate risk: MYC activation without del17p (125 months); high risk: MYC activation + del17p (11 months). Our results show that cytogenetic analysis is a useful diagnostic tool in B-PLL that improves prognostic stratification.

  Study EGAS00001003274

• RNA seq on 19 samples of Radiation-Induced Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002318

• UK10K NEURO EDINBURGH

  In the UK10K project we propose a series of complementary genetic approaches to find new low frequency/rare variants contributing to disease phenotypes. These will be based on obtaining the genome wide sequence of 4000 samples from the TwinsUK and ALSPAC cohorts (at 6x sequence coverage), and the exome sequence (protein coding regions and related conserved sequence) of 6000 samples selected for extreme phenotypes. Our studies will focus primarily on cardiovascular-related quantitative traits, obesity and related metabolic traits, neurodevelopmental disorders and a limited number of extreme clinical phenotypes that will provide proof-of-concept for future familial trait sequencing. We will analyse directly quantitative traits in the cohorts and the selected traits in the extreme samples, and also use imputation down to 0.1% allele frequency to extend the analyses to further sample sets with genome wide genotype data. In each case we will investigate indels and larger structural variants as well as SNPs, and use statistical methods that combine rare variants in a locus or pathway as well as single-variant approaches. This sample set consists of subjects with schizophrenia recruited from psychiatric in-patient and out-patient facilities in Scotland. All diagnoses are based on standard research procedures and family histories are available. Patients have IQ>70 and the cohort includes the following groups: 100 cases with detailed clinical, cognitive and structural and functional neuroimaging phenotypes; 138 familial cases who are the probands of families where DNA has been collected from other affected members; 162 unrelated individuals. In most cases patients and their families may be re contacted to take part in further studies.For further information on this cohort please contact Andrew McIntosh (andrew.mcintosh@ed.ac.uk).

  Study EGAS00001000117

• 18 Whole Exome Sequencing for Radiation Induced-Meningiomas

  Purpose: Majority of pediatric cancers require the irradiation of the central nervous system (CNS), and as more patients survive into adulthood from improved oncological therapy the sequelae of brain radiation are increasing in prevalence. Radiation-induced meningiomas (RIMs), one such secondary effect, demonstrate a clinically more aggressive behaviour than sporadic meningiomas (SMs). We aimed to describe the genomic mutational landscape of RIMs.Methods: We analyzed a principal cohort of 18 RIMs, with 31 RIMs overall, from patients who received childhood radiation therapy and 30 SMs, as a comparator population. We performed a multiplatform integrative genomic analysis; including methylation, whole exome and RNA sequencing. Results: RIMs exhibited a five-fold increase in copy number alterations, commonly the loss of chromosome 1p (17/18 RIMs) and 22q (17/18 RIMs), which was significantly more than observed in sporadic meningiomas. Furthermore, RNA sequencing data revealed an NF2 gene fusion event in 35.3% of RIMs. In all 6 cases, there was a complete NF2 exon spliced into a complete exon of a reciprocal gene, suggesting that the breakpoints of genomic rearrangement are intronic. All tumours with the NF2 fusion also possessed monosomy of chromosome 22q, rendering the cells with homozygous disruption of NF2. Clinically, RIMs with the NF2 fusion exhibited ill-defined borders and a tendency to develop in anatomic frontal location. Also, targeted sequencing panel confirmed that RIMs had fewer nonsynonymous NF2 mutations (6.5% vs. 30% in SM) and absence of mutations in TRAF7, SMO, KLF4, PIK3CA and AKT1, genes traditionally involved in SMs.Conclusion: Our study demonstrates that RIMs have distinct genomic drivers of oncogenesis as compared to SMs, specifically NF2 inactivation through fusion event. Radiation therapy possibly triggers genomic structural rearrangements through error-prone repair of double-stranded DNA breaks.

  Study EGAS00001002317

• Breast cancer women lack normal lifelong immune response after full-term pregnancies

  Immunological tolerance during pregnancy is necessary for women’s bodies to accept the semi-allogenic fetus. Interestingly, “immune evasion”, which consists of some similar immunological changes, was recently proposed as a hallmark of cancer. Looking at these results, it seems paradoxical that increasing number of full-term pregnancies (FTP) reduces the risk of breast cancer in women. Our aim was to use a systems epidemiology approach to investigate this paradox by modelling breast cancer incidence as a function of parity in the Norwegian Women and Cancer (NOWAC) cohort, then testing the mathematical model using gene expression from blood in a subcohort of these women: the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis for immunological gene sets. A linear trend nicely fitted the dataset showing an 8% decrease in risk for each FTP, independent of stratification on other risk factors and lasting for decades after a woman’s last FTP. However, when we looked at gene expression we found that hundreds of genes showed linear trends in cancer-free controls, but this was not the case in /any/ of the samples from breast cancer cases. In the gene set enrichment analysis, samples consisted of human blood or cord blood and mouse bone marrow or spleen. We found more adaptive gene sets than expected in humans and more innate gene sets than expected in mice. None of the gene sets provided information about the long-term effects of immunological tolerance during pregnancy, but the lack of relevant reductionist experiments hampers our interpretation. We suggest that, after resolution at birth, the immunological tolerance induced by pregnancy augments immune response to cancer development.

  Study EGAS00001002616