Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma

DAC for Study EGAS00001005054

DATA ACCESS AGREEMENT This agreement governs the terms of access to the ICG DLBCL Controlled Data (further defined below). In signing this agreement, you agree to be bound by the terms and conditions of access set out therein. The terms of access set out in this agreement apply to the User and to the User Institution(s) (as defined below). The current agreement is limited to the ICG DLBCL Controlled Data (as defined below) and does not cover other data generated at this Institution. Definitions Data: The managed access datasets described in Appendix I, which has been collected and recorded by Dr. Pasqualucci and Dr. Dalla-Favera, and to which the User Institution has requested access. Data Producers: Dr. L Pasqualucci and Dr. R. Dalla-Favera, responsible for the development, organisation, and oversight of these Data. Authorised Personnel: The individuals at the User Institution to whom Dr. Pasqualucci and Dr. Dalla-Favera grant access to the Data. This includes the User, the individuals listed in Appendix II and any other individuals for whom the User Institution subsequently requests access to the Data. Details of the initial Authorised Personnel are set out in Appendix II. External Collaborator: A collaborator of the User, working for an institution other than the User Institution. Research Project: The project for which the User Institution has requested access to these Data. A description of the Project is set out in Appendix II. Publications: Includes, without limitation, articles published in print journals, electronic journals, reviews, books, posters and other written and verbal presentations of research. Research Participant: An individual whose data form part of these Data. Research Purposes: Shall mean research that is seeking to advance the understanding of genetics and genomics, including the treatment of disorders, and work on statistical methods that may be applied to such research. User: An applicant (principal investigator), having signed this Data Access Agreement, whose User Institution has cosigned this Data Access Agreement, both of them having received acknowledgement of its acceptance. User Institution(s): The Institution at which the User is employed, affiliated or enrolled. A representative of it has co-signed this Data Access Agreement with the User and received acknowledgement of its acceptance. 1. The User and the User Institution agree to only use these Data for the purpose of the Project (described in Appendix II) and only for Research Purposes. The User Institution further agrees that it will only use these Data for Research Purposes which are within the limitations (if any) set out in Appendix I. 2. The User and the User Institution agrees to preserve, at all times, the confidentiality of these Data. In particular, it undertakes not to use, or attempt to use these Data to compromise or otherwise infringe the confidentiality of information on Research Participants. Without prejudice to the generality of the foregoing, the User Institution agrees to use at least the measures set out in Appendix I to protect these Data. 3. The User and the User Institution agrees to protect the confidentiality of Research Participants in any research papers or publications that they prepare by taking all reasonable care to limit the possibility of identification. 4. The User and the User Institution agrees not to link or combine these Data to other information or archived data available in a way that could re-identify the Research Participants, even if access to that data has been formally granted to the User Institution or is freely available without restriction. 5. 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The User and the User Institution agrees to follow the Fort Lauderdale Guidelines (http://www.wellcome.ac.uk/stellent/groups/corporatesite/@policy_communications/documents/web_doc ument/wtd003207.pdf) and the Toronto Statement (http://www.nature.com/nature/journal/v461/n7261/full/461168a.html). This includes but is not limited to recognising the contribution of the Data Producers and including a proper acknowledgement in all reports or publications resulting from the use of these Data. 8. The User and the User Institution agrees to follow the Publication Policy in Appendix III. This includes respecting the moratorium period for the Data Producers to publish the first peer-reviewed report describing and analysing these Data. 9. The User and the User Institution agrees not to make intellectual property claims on these Data and not to use intellectual property protection in ways that would prevent or block access to, or use of, any element of these Data, or conclusion drawn directly from these Data. 10. The User and the User Institution can elect to perform further research that would add intellectual and resource capital to these data and decide to obtain intellectual property rights on these downstream discoveries. In this case, the User Institution agrees to implement licensing policies that will not obstruct further research and to follow the U.S. National Institutes of Health Best Practices for the Licensing of Genomic Inventions (2005) in conformity with the Organisation for Economic Co-operation and Development Guidelines for the Licensing of the Genetic Inventions (2006) (http://www.oecd.org/science/biotech/36198812.pdf ). 11. The User and the User Institution agrees to destroy/discard the Data held, once it is no longer used for the Project, unless obliged to retain the data for archival purposes in conformity with audit or legal requirements. 12. The User and the User Institution will notify Dr. Pasqualucci and Dr. Dalla-Favera within 30 days of any changes or departures of Authorised Personnel. 13. The User and the User Institution will notify Dr. Pasqualucci and Dr. Dalla-Favera prior to any significant changes to the protocol for the Project. 14. The User and the User Institution will notify Dr. Pasqualucci and Dr. Dalla-Favera as soon as it becomes aware of a breach of the terms or conditions of this agreement. 15. The User and the User Institution accept that this agreement may be terminated upon any breach of this agreement from the User, the User Institution(s) or any authorized personnel mentioned in section D “Names of authorized personnel” or E “Names of authorized students” of this application document, by written notice to the User Institution. If this agreement terminates for any reason, the User Institution will be required to destroy any Data held, including copies and backup copies. This clause does not prevent the User Institution from retaining these data for archival purpose in conformity with audit or legal requirements. 16. The User and the User Institution accepts that it may be necessary for the Data Producers to alter the terms of this agreement from time to time. As an example, this may include specific provisions relating to the Data required by Data Producers other than Dr. Pasqualucci and Dr. Dalla-Favera. 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Authorized Institutional Representative Name: Title: Affiliation: Institutional email address: Signature: Date: Principal Investigator Name: Title: Affiliation: Institutional email address: Signature: Date: Agreed for COLUMBIA UNIVERSITY Signature: Name: Title: Date: APPENDIX I – DATASET DETAILS APPENDIX II ––PROJECT DETAILS APPENDIX III –– PUBLICATION POLICY APPENDIX I – DATASET DETAILS Dataset reference EGAS00001005054: Genetic analysis of HLA and immune escape genes in Diffuse Large B-cell Lymphoma Name of project that created the dataset Genetic mechanisms of HLA-I loss and immune escape in Diffuse Large B Cell Lymphoma Research project that created the dataset Fifty percent of diffuse large B-cell lymphoma (DLBCL) cases lack cell-surface expression of the class-I major histocompatibility complex (MHC-I), thereby escaping immune recognition by cytotoxic T cells. In order to comprehensively identify the mechanisms involved in MHC-I loss, we first performed immunophenotypic analysis of both MHC class-I and -II in 657 cases across the spectrum of B-NHL, revealing that loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. We then used whole exome and targeted deep-sequencing to examine genes involved in MHC-I expression in 74 DLBCL samples representative of MHC-I positive and negative cases. We show here that somatic biallelic or monoallelic inactivation of B2M and/or HLA-I is present in 80.9% (34/42) of MHC-I negative tumors. Furthermore, 68.8% (22/32) of MHC-I positive DLBCLs also harbored monoallelic HLA-I genetic alterations (MHC-I positivemono) that lead to allelic imbalance, suggesting allele-specific inactivation. Both MHC-I negative and MHC-I positivemono cases showed a significantly higher mutational burden as well as a higher number of inferred neo-antigens, suggesting co-selection of HLA-I loss and sustained neo-antigen production. Interestingly, the analysis of > 500.000 individuals in two databases revealed homozygosity of germline HLA-I genes in 26-38% of DLBCL patients, a frequency significantly higher than that observed in any other cancer type. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counter-selected in the context of oncogene-driven lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multi-step process of HLA-I loss including both germ-line and somatic events in DLBCL development, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease. This study includes 3 datasets: 1) Whole exome sequencing (WES) of 34 DLBCL tumor samples and 32 paired normal samples 2) Whole genome sequencing (WGS) of 10 DLBCL tumor samples and 12 paired normal samples 3) Targeted HLA-I deep sequencing of 26 DLBCL tumor samples and 26 paired normal samples Specific limitations on areas of research Use of the dataset is limited to scientific genetic research related to cancer. The data will only be used for research purposes. Investigators must state in the DAR their intention to publish or otherwise broadly share any findings from their study with the scientific community. This consent group requires IRB approval. Minimum protection measures required File access: Data can be held in unencrypted files on an institutional compute system, with Unix user group read/write access for one or more appropriate groups but not Unix world read/write access behind a secure firewall. Laptops holding these data should have password protected logins and screenlocks (set to lock after 5 min of inactivity). If held on USB keys or other portable hard drives, the data must be encrypted. APPENDIX II – PROJECT DETAILS (to be completed by the Requestor) Genotype Data Requested (i.e., EGA Study and Dataset Accession Number) Title of Project In 30 words or less. Brief abstract of the Project in which the Data will be used (500 words max) Research Question Please provide a clear description of the project and its specific aims in no more than 750 words. This should include specific details of what you plan to do with the data and include key references. Feasibility Please describe your experience and expertise, and that of your collaborators, and how this will be applied to the proposed study. A publication list MUST be provided for the applicant, co-applicants and PhD supervisors where PhD students have applied. The committee needs assurance of competence in handling datasets of this size and nature. All Individuals who the User Institution wishes to be named as registered users Name of Registered User Email Job Title Supervisor All Individuals that should have an account created at the EGA Name of Registered User Email Job Title APPENDIX III – PUBLICATION POLICY Dr. Pasqualucci and Dr. Dalla-Favera intend to publish the results of their analysis of this dataset and do not consider its deposition into public databases to be the equivalent of such publications. Dr. Pasqualucci and Dr. Dalla-Favera anticipate that the dataset could be useful to other qualified researchers for a variety of purposes. However, some areas of work are subject to a publication moratorium. The publication moratorium covers any publications (including oral communications) that describe the use of the dataset. For research papers, submission for publication should not occur until 6 months after these data were first made available on the relevant hosting database, unless Dr. Pasqualucci and Dr. Dalla-Favera has provided written consent to earlier submission. We request that any publications based on these data acknowledge their use by citing their original publication: Fangazio et al., Genetic mechanisms of HLA-I loss and immune escape in Diffuse Large B-Cell Lymphoma, in revision. and describing how the data can be accessed, including the name of the hosting database (The European Genome-phenome Archive at the European Bioinformatics Institute) and its accession number (EGAS00001005054).