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• Structural rearrangements generate cell-specific, gene-independent CRISPR-Cas9 loss of fitness effects.

  CRISPR-Cas9 genome editing is widely used to study gene function, from basic biology to biomedical research. Structural rearrangements are a ubiquitous feature of cancer cells and their impact on the functional consequences of CRISPR-Cas9 gene-editing has not yet been assessed. Utilizing CRISPR-Cas9 knockout screens for 250 cancer cell lines, we demonstrate that targeting structurally rearranged regions, in particular tandem or interspersed amplifications, is highly detrimental to cellular fitness in a gene independent manner. In contrast, amplifications caused by whole chromosomal duplications have little to no impact on fitness. This effect is cell line specific and dependent on the ploidy status. We devise a copy-number ratio metric that substantially improves the detection of gene-independent cell fitness effects in CRISPR-Cas9 screens. Furthermore, we develop a computational tool, called Crispy, to account for these effects on a single sample basis and provide corrected gene fitness effects. Our analysis demonstrates the importance of structural rearrangements in mediating the effect of CRISPR-Cas9-induced DNA damage, with implications for the use of CRISPR-Cas9 gene-editing in cancer cells.

  Dataset EGAD00001004124

• All you need to know about our new DAC Portal

  With the DAC Portal, it is possible to streamline the process of managing access to sensitive data, ensuring that researchers have the necessary resources to advance scientific discovery while maintaining the highest standards of data protection and privacy. We know that, as a new tool, its first use can be complex. For this reason, in this article we will try to show all the elements of interest. Enjoy! Credentials: who needs to create a new user to access the DAC Portal and who doesn't? Only new users (since September the 12th) need to create an EGA account to access the DAC Portal. The EGA team went one step ahead by creating EGA accounts for former DAC members to login to the DAC Portal. These accounts are linked to the personal email used in the DAC structure: To check the linked email, DAC members can paste the DAC ID right after this link: https://metadata.ega-archive.org/dacs/ (e.g. https://metadata.ega-archive.org/dacs/EGAC00001002543) In case of password oblivion, it is possible to set a new one. All the process is channelled through the personal email. Some DAC members may be interested in updating the DAC email. This action can be done contacting our Helpdesk team. For the correct functioning of the DAC Portal, users must add the missing information of the DAC Profile. For a deeper dive, check out our documentation. The first step: knowing your workspace on the Portal Once logged in to the platform using the EGA User credentials, note the sections available: DACs and Policies. In the first one it is possible to check all user's registered DACs by default. It provides a comprehensive overview of each DAC, including its EGA accessions (EGAC), title, status, and the number of data access requests associated with each DAC. Whereas the Policies section is where users can manage and view all their registered policies, along with their associated EGA accessions, links, and titles. A drop-down menu is available with shortcuts to the most useful pages in the top right corner. It is possible to check DACs and policies, as well as creating new ones. In this menu, users can also contact the Helpdesk team using the “Need Help?” section to make inquiries about DACs and policies. Comprehending the DACs list & making the most of all the features Colours are crucial in the DAC's section as they will indicate the user role and the status in every committee, namely: Yellow: you are the administrator of the DAC and have full control to add other contacts, modify the content, and manage data access requests. Orange: you are a member of the DAC and have the authority to manage data access requests but cannot make any changes to the content. Blue: you have been invited to join the DAC and need to either accept or decline the invitation. Grey: the DAC is currently pending validation by the EGA Helpdesk team. Red: the DAC has been declined by the EGA Helpdesk team. Discover more information on how to view the message from Helpdesk containing the declination reason or how to validate or reject a DAC invitation by taking the tour of the DAC Portal. How to create, register and edit a DAC Creating a DAC is an easy process that only requires users to complete the necessary information. After that, the EGA Helpdesk team will review the proposal and validate the proposal. Once the DAC is validated it is possible for authorised users with admin role to edit it at any time, ensuring that all information and contacts associated with the committee is accurate and up to date. Membership management is controlled by searching for the EGA user looking for their username, email, or organisation. Please, note that for a person's details to appear in this search engine, they must have registered as a EGA user. Data Access Committee administrators manage two types of permissions that apply to contacts: Main contact and Role. Both can be modified at any time: Main contact refers to the primary person we firstly contact for any inquiry about the DAC (please, note that we can contact all DAC members, and this refers to the person we will contact first). Role defines the actions that can be taken by each contact. There are two possible status, admin and member, details of which can be found in the Take the Tour. Keep in mind that, to save the modifications, it is always necessary to click on “Update”. Moreover, it is also possible to delete any contact in a DAC whenever it is needed. The data request process: how to manage access requests The data request process is now channelled through the EGA website. Once a user sends a request access, the petition will go directly to the DAC Portal profile of the DAC members liked to the requested dataset. Whenever a request is received, a sand clock symbol will be displayed next to the DAC responsible for the dataset involved. By clicking on the DAC, it is possible to discover more information about requester(s). In this section, DAC Portal users will also be able to modify the display of the data access requests. It is possible to group requests by dataset accession or username, depending on the user preferences. Additionally, it is possible to isolate specific requests by user or dataset. To accept a request, users must slide the button to the right. Once the button turns green, it signifies that the request is accepted; the requester will be granted access to the requested dataset. To make lives easier, we have implemented a “Select all” button to easily accept or revoke multiple requests at once. To decline requests, it is necessary to slide the button to the left. A red button means the requester will not be granted access to the dataset. The DAC Portal will always ask to submit the reason why the data access was denied. Please, note that any decision, grant or denial, must be confirmed clicking the "Apply" button. This will update the status of the request and notify the requester accordingly. Taking control of the activity in the DAC Portal: checking the requests history The History button is a useful feature that allows users to access a list of all the requests that have been granted. This is especially useful for auditing purposes, as it enables to keep track of who has been granted access to the data and when. To facilitate control for those users with several requests we have included a filtering option. It allows to filter requests by user, mail, dataset, EGA ID, and date (these are combinable to boost the search). Don't forget about policies: creation, management, and update Similarly to the DACs section, in the Policies one users can manage and view all their registered policies. By clicking on any policy, it is possible to view its details as well as making any necessary updates or modifications. The sheets symbol and its adjacent number indicate the quantity of objects using a policy. By clicking in the location symbol users will go directly to the DAC page on the DAC Portal to see more information about that DAC. DAC Portal users can create new policies. The first step requires to link the policy to a registered DAC. After defining the title, users can either add a link to an external URL containing terms & conditions or write the policy content directly on the DAC Portal. Keep in mind that both options can be included. Data Use Ontology (DUO) codes can be added to new policies. These codes are used to specify the permitted and prohibited uses of the data. Please, note that some of them require a modifier to provide additional specificity. Find out more by checking out this specific content on the DAC Portal Tour. Policies can be modified at any given time by clicking on one registered policy, which will display the current information.

  Blog new-dac-portal

• Detection of Colorectal Cancer Susceptibility Loci Using Genome-Wide Sequencing

  The Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) is a collaborative effort comprised of a coordinating center and scientific researchers from well-characterized cohort and case-control studies. This international consortium aims to accelerate the discovery of common and rare genetic risk variants for colorectal cancer by conducting large-scale meta-analyses of existing and newly generated genome-wide association study (GWAS) data, whole genome sequencing, replicating and fine-mapping of genetic discoveries, and investigating how genetic risk variants are modified by environmental risk factors. To expand these efforts, we assembled case-control sets or nested case-control sets from 6 different North American or European studies. Summary descriptions and study participant inclusions/exclusion criteria for each of these studies are detailed below. Cancer Prevention Study II (CPS II): The CPS II Nutrition cohort is a prospective study of cancer incidence and mortality in the United States, established in 1992 and described in detail elsewhere (Calle et al., 2002 PMID:12015775; Campbell et al., 2014 PMID:25472679). At enrollment, participants completed a mailed self-administered questionnaire including information on demographic, medical, diet, and lifestyle factors. Follow-up questionnaires to update exposure information and to ascertain newly diagnosed cancers were sent biennially starting in 1997. Reported cancers were verified through medical records, state cancer registry linkage, or death certificates. The Emory University Institutional Review Board approves all aspects of the CPS II Nutrition Cohort. We restricted to samples that had blood DNA source. Controls were matched to cases in a case/control ratio of 2:1 on reference year and sex. Darmkrebs: Chancen der Verhütung durch Screening (DACHS): This German study was initiated as a large population-based case-control study in 2003 in the Rhine-Neckar-Odenwald region (southwest region of Germany) to assess the potential of endoscopic screening for reduction of colorectal cancer risk and to investigate etiologic determinants of disease, particularly lifestyle/environmental factors and genetic factors. Cases with a first diagnosis of invasive colorectal cancer (International Classification of Diseases 10 codes C18-C20) who were at least 30 years of age (no upper age limit), German speaking, a resident in the study region, and mentally and physically able to participate in a one-hour interview, were recruited by their treating physicians either in the hospital a few days after surgery, or by mail after discharge from the hospital. Cases were confirmed based on histologic reports and hospital discharge letters following diagnosis of colorectal cancer. All hospitals treating colorectal cancer patients in the study region participated. Based on estimates from population-based cancer registries, more than 50% of all potentially eligible patients with incident colorectal cancer in the study region were included. Community-based controls were randomly selected from population registries, employing frequency matching with respect to age (5-year groups), sex, and county of residence. Controls with a history of colorectal cancer were excluded. Controls were contacted by mail and follow-up calls. The participation rate was 51%. During an in-person interview, data were collected on demographics, medical history, family history of CRC, and various life-style factors, as were blood and mouthwash samples. Routine formalin-fixed, paraffin-embedded (FFPE) tumor samples from the patients enrolled were requested from the pathology institutes and used for tumor tissue analyses. This analysis includes participants with blood source DNA that were recruited up to 2010 in this ongoing study. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Health Professionals Follow-up Study (HPFS): A parallel prospective study to the NHS (Nurses' Health Study). The HPFS cohort comprised 51,529 men aged 40-75 who, in 1986, responded to a mailed questionnaire (Rimm et al., 1990 PMID:2090285). Participants provided information on health related exposures, including current and past smoking history, age, weight, height, diet, physical activity, aspirin use, and family history of colorectal cancer. Colorectal cancer and other outcomes were reported by participants or next-of-kin and were followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical record review. Information was abstracted on histology and primary location. Incident cases were defined as those occurring after the subject provided the blood sample. Prevalent cases were defined as those occurring after enrollment in the study but before the subject provided the blood sample. Follow-up evaluation has been excellent, with 94% of the men responding to date. Colorectal cancer cases were ascertained through January 1, 2008. In 1993-1995, 18,825 men in the HPFS mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 13,956 men in the HPFS who had not provided a blood sample previously mailed in a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1986, but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. Control participants were required to be free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Nurses Health Study (NHS): The NHS cohort began in 1976 when 121,700 married female registered nurses age 30-55 years returned the initial questionnaire that ascertained a variety of important health-related exposures (Belanger et al., 1978 PMID:248266). Since 1976, follow-up questionnaires have been mailed every 2 years. Colorectal cancer and other outcomes were reported by participants or next-of-kin and followed up through review of the medical and pathology record by physicians. Overall, more than 97% of self-reported colorectal cancers were confirmed by medical-record review. Information was abstracted on histology and primary location. The rate of follow-up evaluation has been high: as a proportion of the total possible follow-up time, follow-up evaluation has been more than 92%. Colorectal cancer cases were ascertained through June 1, 2008. In 1989-1990, 32,826 women in NHS I mailed blood samples by overnight courier, which were aliquoted into buffy coat and stored in liquid nitrogen. In 2001-2004, 29,684 women in NHS I who did not previously provide a blood sample mailed a swish-and-spit sample of buccal cells. Incident cases were defined as those occurring after the subject provided a blood or buccal sample. Prevalent cases were defined as those occurring after enrollment in the study in 1976 but before the subject provided either a blood or buccal sample. Participants with histories of cancer (except nonmelanoma skin cancer), ulcerative colitis, or familial polyposis, case-control sets were excluded. For this study, only European ancestry participants with blood source DNA and incident colorectal cancer cases were eligible for selection. Since enrollment year and sex matched exactly, controls were randomly selected in a case/control ratio of 2:1. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trail (PLCO): PLCO enrolled 154,934 participants (men and women, aged between 55 and 74 years) at ten centers into a large, randomized, two-arm trial to determine the effectiveness of screening to reduce cancer mortality. Sequential blood samples were collected from participants assigned to the screening arm. Participation was 93% at the baseline blood draw. White colorectal cancer cases with a family history of colorectal cancer (no history of ulcerative colitis, Crohn's Disease, diverticulitis, Gardner's syndrome, Familial Polyposis) and successful genotyping from previous Peters GWAS were selected for this project. Controls were matched to cases on reference age and sex in a case/control ratio of 2:1. Women's Health Initiative (WHI): WHI is a long-term national health study that has focused on strategies for preventing heart disease, breast and colorectal cancer, and osteoporotic fractures in postmenopausal women. The original WHI study included 161,808 postmenopausal women enrolled between 1993 and 1998. The Fred Hutchinson Cancer Research Center in Seattle, WA serves as the WHI Clinical Coordinating Center for data collection, management, and analysis of the WHI. The WHI has two major parts: a partial factorial randomized Clinical Trial (CT) and an Observational Study (OS); both were conducted at 40 Clinical Centers nationwide. The CT enrolled 68,132 postmenopausal women between the ages of 50-79 into trials testing three prevention strategies. If eligible, women could choose to enroll in one, two, or all three of the trial components. The components are: Hormone Therapy Trials (HT): This double-blind component examined the effects of combined hormones or estrogen alone on the prevention of coronary heart disease and osteoporotic fractures, and associated risk for breast cancer. Women participating in this component with an intact uterus were randomized to estrogen plus progestin (conjugated equine estrogens [CEE], 0.625 mg/d plus medroxyprogesterone acetate [MPA] 2.5 mg/d) or a matching placebo. Women with prior hysterectomy were randomized to CEE or placebo. Both trials were stopped early, in July 2002 and March 2004, respectively, based on adverse effects. All HT participants continued to be followed without intervention until close-out. Dietary Modification Trial (DM): The Dietary Modification component evaluated the effect of a low-fat and high fruit, vegetable and grain diet on the prevention of breast and colorectal cancers and coronary heart disease. Study participants were randomized to either their usual eating pattern or a low-fat dietary pattern. Calcium/Vitamin D Trial (CaD): This double-blind component began 1 to 2 years after a woman joined one or both of the other clinical trial components. It evaluated the effect of calcium and vitamin D supplementation on the prevention of osteoporotic fractures and colorectal cancer. Women in this component were randomized to calcium (1000 mg/d) and vitamin D (400 IU/d) supplements or a matching placebo. The Observational Study (OS) examines the relationship between lifestyle, environmental, medical and molecular risk factors and specific measures of health or disease outcomes. This component involves tracking the medical history and health habits of 93,676 women not participating in the CT. Recruitment for the observational study was completed in 1998 and participants were followed annually for 8 to 12 years. All centrally confirmed White cases of invasive colorectal cancer, or death from colorectal cancer were selected as potential cases from the March, 2011 database. Case priory lists are: 1) have positive family history of colorectal cancer; 2) randomly select cases until we get a total of n=800 cases. Control participants were required to be White, free of invasive colorectal cancer and non-invasive (stage 0 in situ) colorectal cancer. Centrally denied cases of colorectal cancer were not allowed into the control pool. Case and control participants were subject to the following exclusion criteria: (1) had prior history of colorectal cancer at baseline; (2) had no available DNA (DNA searching as Nov 15, 2012); (3) cannot be deposited to dbGaP; (4) lost to follow-up after enrollment; (5) selected for WHI study M26 Phase II. Controls were matched to cases in a case/control ratio of 2:1. In order to get 2 cases with 1 control, cases were grouped by enrollment year (a total of 5 groups). For each year group, around 50% cases were selected to match controls. In total, 401 cases were selected to match controls. Matching was done on enrollment year, which was matched exactly. For additional information, see dbGaP: phs000200 and ClinicalTrials: NCT00000611.

  Study phs001554

• National Human Genome Research Institute (NHGRI) GENEVA Genome-Wide Association Study of Venous Thrombosis (GWAS of VTE)

  Overview: Our overall long-term goal is to determine risk factors for the complex (multifactorial) disease, venous thromboembolism (VTE), that will allow physicians to stratify individual patient risk and target VTE prophylaxis to those who would benefit most. In this genome-wide association case-control study (1300 cases and 1300 controls) we hope to identify susceptibility variants for VTE. Mutations within genes encoding for important components of the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways are risk factors for VTE. We hypothesize that other genes within these four pathways or within other pathways also are VTE disease-susceptibility genes. Therefore, we performed a genome wide association (GWA) screen and analysis using the Illumina 660W platform to identify SNPs within 1,300 clinic-based, non-cancer VTE cases primarily from Minnesota and the upper Midwest USA, and 1300 clinic-based, unrelated controls frequency-matched on patient age, gender, myocardial infarction/stroke status and state of residence. This is a subset of a slightly larger candidate gene study using 1500 case-control pairs to identify haplotype-tagging SNPs (ht-SNPs) in a large set of candidate genes (n~750) within the anticoagulant, procoagulant, fibrinolytic, and innate immunity pathways. Study Populations. Cases. VTE cases were consecutive Mayo Clinic outpatients with objectively-diagnosed deep vein thrombosis (DVT) and/or pulmonary embolism (PE) residing in the upper Midwest and referred by Mayo Clinic physician to the Mayo Clinic Special Coagulation Laboratory for clinical diagnostic testing to evaluate for an acquired or inherited thrombophilia, or to the Mayo Clinic Thrombophilia Center. Any person contacted to be a control but discovered to have had a VTE was evaluated for inclusion as a case. Cases were primarily residents from Minnesota, Wisconsin, Iowa, Michigan, Illinois, North or South Dakota, Nebraska, Kansas, Missouri and Indiana. A DVT or PE was categorized as objectively diagnosed when (a) confirmed by venography or pulmonary angiography, or pathology examination of thrombus removed at surgery, or (b) if at least one non-invasive test (compression duplex ultrasonography, lung scan, computed tomography scan, magnetic resonance imaging) was positive. A VTE was defined as: Proximal leg deep vein thrombosis (DVT), which includes the common iliac, internal iliac, external iliac, common femoral, superficial [now termed "femoral"] femoral, deep femoral [sometimes referred to as "profunda" femoral] and/or popliteal veins. (Note: greater and lesser saphenous veins, or other superficial or perforator veins, were not included as proximal or distal leg DVT). Distal leg DVT (or "isolated calf DVT"), which includes the anterior tibial, posterior tibial and/or peroneal veins. (Note: gastrocnemius, soleal and/or sural [e.g., "deep muscular veins" of the calf] vein thrombosis was not included as distal leg DVT). Arm DVT, which includes the axillary, subclavian and/or innominate (brachiocephalic) veins. (Note: jugular [internal or external], cephalic and brachial vein thrombosis was not included in "arm DVT"). Hepatic, portal, splenic, superior or inferior mesenteric, and/or renal vein thrombosis. (Note: ovarian, testicular, peri-prostatic and/or pelvic vein thrombosis was not included). Cerebral vein thrombosis (includes cerebral or dural sinus or vein, saggital sinus or vein, and/or transverse sinus or vein thrombosis). Inferior vena cava (IVC) thrombosis Superior vena cava (SVC) thrombosis Pulmonary embolism Patients with VTE related to active cancer, antiphospholipid syndrome, inflammatory bowel disease, vasculitis, a rheumatoid or other autoimmune disorder, a vascular anomaly (e.g., Klippel-Trénaunay syndrome, etc.), heparin-induced thrombocytopenia, or a mechanical cause for DVT (e.g., arm DVT or SVC thrombosis related to a central venous catheter or transvenous pacemaker, portal and/or splenic vein thrombosis related to liver cirrhosis, IVC thrombosis related to retroperitoneal fibrosis, etc.), with hemodialysis arteriovenous fistula thrombosis, or with prior liver or bone marrow transplantation were excluded. Controls. A Mayo Clinic outpatient control group was prospectively recruited for this study. Controls were frequency-matched on the age group (18-29, 30-39, 40-49, 50-59, 60-69, 70-79, and 80+ years), sex, myocardial infarction/stroke status, and state of residence distribution of the cases. We selected clinic-based controls using a controls' database of persons undergoing general medical examinations in the Mayo Clinic Departments of General Internal Medicine or Primary Care Internal Medicine. Additionally persons undergoing evaluation at the Mayo Clinic Sports Medicine Center, and the Department of Family Medicine were screened for inclusion as controls. This study is part of the Gene Environment Association Studies initiative (GENEVA, http://www.genevastudy.org) funded by the trans-NIH Genes, Environment, and Health Initiative (GEI). The overarching goal is to identify novel genetic factors that contribute to venous thrombosis through large-scale genome-wide association studies of 1,300 clinic-based, VTE cases and 1300 clinic-based, unrelated controls. Genotyping was performed at the Johns Hopkins University Center for Inherited Disease Research (CIDR). Data cleaning and harmonization were done at the GEI-funded GENEVA Coordinating Center at the University of Washington.

  Study phs000289

• MBD4 targeted sequencing

  We sequenced a gene of interest, MBD4, in both germline (n=1099) and tumor (n=192) sample from Uveal Melanoma patients.

  Study EGAS00001005012

• Tanzania dietary intervention study 2019-2020

  We performed a dietary intervention study comparing western diet, traditional diet and the supplementation of fermented banana beverage in a cohort of 66 individuals (22 in each study arm).

  Dataset EGAD50000000457

• Human non-malignant plasma cfRNA study - raw data

  mRNA capture sequencing on plasma sample from 88 patients with a non-malignant disease and from 37 healthy donors.

  Study EGAS50000001264

• Compound heterozygous variants in LAMC3 in association with posterior periventricular nodular heterotopia

  Periventricular nodular heterotopia is a malformation of cortical development characterized by nodules of abnormally migrated neurons.

  Study EGAS00001004793

• A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  A molecular signature for IL-10-producing Th1 cells in protozoan parasitic diseases

  Dataset EGAD00001007532

• Characterization of a novel MEF2D-BCL9 fusion positive acute lymphoblastic leukemia cell line WXS

  A novel in-house-made pediatric MEF2D-BCL9 fusion positive acute lymphoblastic leukemia cell line was characterized

  Dataset EGAD00001009758