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MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carry MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that they lead to TMZ resistance both in vitro and in vivo. Lastly we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

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CGGA Data Access Policy

This policy governs the terms of access to the de-identified dataset consisting of RNA sequencing data from temozolomide treated recurrent glioma patients generated at BNI under the direction of Tao Jiang, Ph.D. 1. Responsibility of Research The Data Set was collected in accordance with applicable laws, regulations, patient consent forms and authorizations pursuant to Institutional Review Board (IRB) approval. 2. Responsibility of Data Recipient Data Recipient agrees that: a. the Data Set shall be used solely for the Study described in Section A; b. any additional uses of the Data Set by the Data Recipient shall be covered under a separate agreement; c. the Data Set shall be used in compliance with all applicable local, state and federal statutes and regulations; d. the Data Set shall be used only at the Institution by the Principal Investigator and the Other Users working under his/her direct supervision; Principal Investigator will notify the BJNI Principal Investigator of any departures of the Principal Investigator or Other Users within 30 days of the changes made. e. the Data Set shall not be transferred, in whole or in part, to anyone outside the Institution without prior written consent of BNI. f. Data Recipient will not contact or make any effort to identify individuals who are or may be included in the Data Set. 3. Confidentiality Data Recipient shall not disclose the Data Set to anyone except the Principal Investigator and the Other Users for the purposes of the Study. The Data Recipient will use the Data Set only in the conduct of the Study and evaluation of its results. Data Recipient agrees to preserve, at all times, the confidentiality of the Data Set. Data Recipient will use the Data Set in a secure manner using appropriate administrative, physical storage and technical safeguards to prevent use or disclosure of the data other than as provided for in this Agreement. Data Recipient agrees to notify the BNI Principal Investigator within 5 days of becoming aware of any use or disclosure of the Data Set in violation of this Agreement. 4. Publication Data Recipient agrees to acknowledge the BNI Principal Investigator in any publication, presentation, abstract or other work based in whole or in part on the Data Set. Data Recipient will cite the BNI Secondary GBM Genomics Data Set as the source of the data in the methods (Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor). 5. Intellectual Property Inventorship of inventions invented by Data Recipient in the performance of the Study (“Inventions”) shall be determined according to P.R China patent law and ownership will vest in the party to whom the inventor has an obligation to assign all right, title and interest in the Invention. Nothing in this Agreement grants Data Recipient any rights to use the Data Set for commercial purposes. BNI explicitly retains ownership of the Data Set and this Agreement does not restrict BNI’s right to distribute the Data Set to other entities. Notwithstanding the foregoing, Data Recipient shall not pursue intellectual property rights which occur as a result of the use of the Data Set in the performance of the Study without first notifying BNI so that BNI can assert claims to legal inventorship under P.R. China law. Data Recipient agrees not to make intellectual property claims on the Data Set and not to use intellectual property protection in ways that would prevent or block access to the Data Set. This Agreement in no way alters any rights or interests of the P.R. China government. 6. Limitation of Liability THE DATA SET IS EXPERIMENTAL IN CELL AND IS BEING MADE AVAILABLE TO RECIPIENT WITH NO WARRANTIES, EXPRESS OR IMPLIED, OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE OR OTHERWISE. IN PARTICULAR, BNI DOES NOT REPRESENT OR WARRANT THAT THE USE OF THE DATA SET WILL NOT INFRINGE OR VIOLATE ANY PATENT OR PROPRIETARY RIGHTS OF THIRD PARTIES. To the extent permitted by law, Institution assumes all liability for damages which may arise from the use, storage or disposal of the Data Set by Data Recipient. BNI (including, but not limited to, its directors, trustees, officers employees, students and agents, as applicable), will not be liable to the Data Recipient for any loss, claim or demand made by or against the Data Recipient or Other Users, due to or arising from the use of the Data Set by the Data Recipient or Other Users or due to unavailability of or interruption in Data Set access for whatever reason, except to the extent caused by the gross negligence or willful misconduct of the BNI. To the extent allowable under applicable laws, Institution agrees to indemnify, defend and hold harmless BNI and its trustees, officers, staff, representatives and agents against all damages, expenses (including without limitation legal expenses), claims, demands, suits or other actions arising from Data Recipient’s acceptance, storage, use and disposal of the Data Set, but only in proportion to and to the extent such are caused by or result from the negligent or intentional acts or omissions of Data Recipient, Other Users, or Institution’s officers, agents or employees. 7. Assignment. This agreement is not assignable by Institution. 8. Term and Termination The term of this agreement shall commence on the Effective Date and shall continue for as long as the Data Recipient retains the Data Set, unless terminated sooner as set forth in this Agreement. The Data Recipient may terminate this Agreement at any time by notifying the BNI Principal Investigator. BNI may terminate this Agreement at any time upon breach of this Agreement by Data Recipient. In the event of termination, Data Recipient shall destroy the Data Set and all copies in its possession, including all documents created by Data Recipient where portions of the Data Set are reproduced. 9. Agreement If Data Recipient agrees to the above terms and conditions for access to the Data Set, please so indicate by returning one copy of this Agreement signed by a duly authorized representative of Institution and by Principal Investigator. Upon receipt of signed Agreement by Institution and Principal Investigator, access to the Data Set will be provided to the Principal Investigator. Principal Investigator agrees to distribute a copy of this agreement and explain its content to any Other Users, and will ensure that they acknowledge their obligations to abide by the terms of this Agreement in their use of the Data Set.

Studies are experimental investigations of a particular phenomenon, e.g., case-control studies on a particular trait or cancer research projects reporting matching cancer normal genomes from patients.

Study ID Study Title Study Type
EGAS00001004544 Other

This table displays only public information pertaining to the files in the dataset. If you wish to access this dataset, please submit a request. If you already have access to these data files, please consult the download documentation.

ID File Type Size Located in
EGAF00004172451 fastq.gz 3.8 GB
EGAF00004172452 fastq.gz 4.1 GB
EGAF00004172453 fastq.gz 1.2 GB
EGAF00004172454 fastq.gz 1.2 GB
EGAF00004172455 fastq.gz 4.0 GB
EGAF00004172456 fastq.gz 4.4 GB
EGAF00004172457 fastq.gz 1.6 GB
EGAF00004172458 fastq.gz 1.6 GB
EGAF00004172459 fastq.gz 3.0 GB
EGAF00004172460 fastq.gz 3.3 GB
EGAF00004172461 fastq.gz 3.8 GB
EGAF00004172462 fastq.gz 4.1 GB
EGAF00004172463 fastq.gz 4.6 GB
EGAF00004172464 fastq.gz 5.0 GB
EGAF00004172465 fastq.gz 1.5 GB
EGAF00004172466 fastq.gz 1.5 GB
EGAF00004172467 fastq.gz 2.9 GB
EGAF00004172468 fastq.gz 3.1 GB
EGAF00004172469 fastq.gz 3.0 GB
EGAF00004172470 fastq.gz 3.3 GB
EGAF00004172471 fastq.gz 3.3 GB
EGAF00004172472 fastq.gz 3.6 GB
EGAF00004172473 fastq.gz 3.6 GB
EGAF00004172474 fastq.gz 3.8 GB
EGAF00004172475 fastq.gz 2.8 GB
EGAF00004172476 fastq.gz 3.1 GB
EGAF00004172477 fastq.gz 4.1 GB
EGAF00004172478 fastq.gz 4.5 GB
EGAF00004172479 fastq.gz 2.4 GB
EGAF00004172480 fastq.gz 2.4 GB
EGAF00004172481 fastq.gz 3.8 GB
EGAF00004172482 fastq.gz 4.5 GB
EGAF00004172483 fastq.gz 4.3 GB
EGAF00004172484 fastq.gz 4.9 GB
EGAF00004172485 fastq.gz 3.2 GB
EGAF00004172486 fastq.gz 3.2 GB
EGAF00004172487 fastq.gz 4.7 GB
EGAF00004172488 fastq.gz 5.2 GB
EGAF00004172489 fastq.gz 1.7 GB
EGAF00004172490 fastq.gz 1.8 GB
EGAF00004172491 fastq.gz 2.6 GB
EGAF00004172492 fastq.gz 2.6 GB
EGAF00004172493 fastq.gz 2.9 GB
EGAF00004172494 fastq.gz 3.4 GB
EGAF00004172495 fastq.gz 4.4 GB
EGAF00004172496 fastq.gz 4.6 GB
EGAF00004172497 fastq.gz 3.9 GB
EGAF00004172498 fastq.gz 4.4 GB
EGAF00004172499 fastq.gz 1.5 GB
EGAF00004172500 fastq.gz 1.5 GB
EGAF00004172501 fastq.gz 4.2 GB
EGAF00004172502 fastq.gz 4.6 GB
EGAF00004172503 fastq.gz 3.8 GB
EGAF00004172504 fastq.gz 4.3 GB
EGAF00004172505 fastq.gz 3.2 GB
EGAF00004172506 fastq.gz 3.6 GB
EGAF00004172507 fastq.gz 3.1 GB
EGAF00004172508 fastq.gz 3.4 GB
EGAF00004172509 fastq.gz 5.2 GB
EGAF00004172510 fastq.gz 5.4 GB
EGAF00004172511 fastq.gz 3.6 GB
EGAF00004172512 fastq.gz 3.8 GB
EGAF00004172513 fastq.gz 2.8 GB
EGAF00004172514 fastq.gz 3.2 GB
EGAF00004172515 fastq.gz 3.6 GB
EGAF00004172516 fastq.gz 3.9 GB
EGAF00004172517 fastq.gz 1.2 GB
EGAF00004172518 fastq.gz 1.2 GB
EGAF00004172519 fastq.gz 1.8 GB
EGAF00004172520 fastq.gz 1.8 GB
EGAF00004172521 fastq.gz 3.0 GB
EGAF00004172522 fastq.gz 3.3 GB
EGAF00004172523 fastq.gz 3.5 GB
EGAF00004172524 fastq.gz 3.9 GB
EGAF00004172525 fastq.gz 3.4 GB
EGAF00004172526 fastq.gz 3.8 GB
EGAF00004172527 fastq.gz 3.2 GB
EGAF00004172528 fastq.gz 3.5 GB
EGAF00004172529 fastq.gz 4.3 GB
EGAF00004172530 fastq.gz 4.5 GB
EGAF00004172531 fastq.gz 4.6 GB
EGAF00004172532 fastq.gz 4.5 GB
EGAF00004172533 fastq.gz 2.6 GB
EGAF00004172534 fastq.gz 2.7 GB
EGAF00004172535 fastq.gz 4.7 GB
EGAF00004172536 fastq.gz 5.3 GB
EGAF00004172537 fastq.gz 3.4 GB
EGAF00004172538 fastq.gz 3.7 GB
EGAF00004172539 fastq.gz 1.3 GB
EGAF00004172540 fastq.gz 1.4 GB
EGAF00004172541 fastq.gz 3.0 GB
EGAF00004172542 fastq.gz 3.2 GB
EGAF00004172543 fastq.gz 3.8 GB
EGAF00004172544 fastq.gz 4.0 GB
EGAF00004172545 fastq.gz 3.6 GB
EGAF00004172546 fastq.gz 4.0 GB
EGAF00004172547 fastq.gz 3.7 GB
EGAF00004172548 fastq.gz 4.1 GB
EGAF00004172549 fastq.gz 3.8 GB
EGAF00004172550 fastq.gz 4.2 GB
EGAF00004172551 fastq.gz 2.1 GB
EGAF00004172552 fastq.gz 2.1 GB
EGAF00004172553 fastq.gz 4.1 GB
EGAF00004172554 fastq.gz 4.6 GB
EGAF00004172555 fastq.gz 2.8 GB
EGAF00004172556 fastq.gz 3.0 GB
EGAF00004172557 fastq.gz 3.6 GB
EGAF00004172558 fastq.gz 4.1 GB
EGAF00004172559 fastq.gz 3.4 GB
EGAF00004172560 fastq.gz 3.8 GB
EGAF00004172561 fastq.gz 2.8 GB
EGAF00004172562 fastq.gz 3.2 GB
EGAF00004172563 fastq.gz 1.8 GB
EGAF00004172564 fastq.gz 1.8 GB
EGAF00004172565 fastq.gz 1.4 GB
EGAF00004172566 fastq.gz 1.5 GB
EGAF00004172567 fastq.gz 2.2 GB
EGAF00004172568 fastq.gz 2.3 GB
EGAF00004172569 fastq.gz 3.1 GB
EGAF00004172570 fastq.gz 3.2 GB
EGAF00004172571 fastq.gz 1.9 GB
EGAF00004172572 fastq.gz 2.0 GB
EGAF00004172573 fastq.gz 1.4 GB
EGAF00004172574 fastq.gz 1.5 GB
EGAF00004172575 fastq.gz 3.8 GB
EGAF00004172576 fastq.gz 4.1 GB
EGAF00004172577 fastq.gz 3.7 GB
EGAF00004172578 fastq.gz 4.0 GB
EGAF00004172579 fastq.gz 1.4 GB
EGAF00004172580 fastq.gz 1.4 GB
EGAF00004172581 fastq.gz 3.4 GB
EGAF00004172582 fastq.gz 3.8 GB
EGAF00004172583 fastq.gz 3.3 GB
EGAF00004172584 fastq.gz 3.6 GB
EGAF00004172585 fastq.gz 3.5 GB
EGAF00004172586 fastq.gz 4.1 GB
EGAF00004172587 fastq.gz 3.1 GB
EGAF00004172588 fastq.gz 3.4 GB
EGAF00004172589 fastq.gz 3.1 GB
EGAF00004172590 fastq.gz 3.5 GB
EGAF00004172591 fastq.gz 2.8 GB
EGAF00004172592 fastq.gz 3.0 GB
EGAF00004172593 fastq.gz 3.5 GB
EGAF00004172594 fastq.gz 3.8 GB
EGAF00004172595 fastq.gz 3.5 GB
EGAF00004172596 fastq.gz 3.7 GB
EGAF00004172597 fastq.gz 2.0 GB
EGAF00004172598 fastq.gz 2.0 GB
EGAF00004172599 fastq.gz 4.3 GB
EGAF00004172600 fastq.gz 4.8 GB
EGAF00004172601 fastq.gz 3.7 GB
EGAF00004172602 fastq.gz 4.3 GB
EGAF00004172603 fastq.gz 3.6 GB
EGAF00004172604 fastq.gz 3.8 GB
EGAF00004172605 fastq.gz 3.5 GB
EGAF00004172606 fastq.gz 4.0 GB
EGAF00004172607 fastq.gz 2.9 GB
EGAF00004172608 fastq.gz 3.3 GB
EGAF00004172609 fastq.gz 4.7 GB
EGAF00004172610 fastq.gz 5.4 GB
EGAF00004172611 fastq.gz 3.1 GB
EGAF00004172612 fastq.gz 3.4 GB
EGAF00004172613 fastq.gz 3.0 GB
EGAF00004172614 fastq.gz 3.2 GB
EGAF00004172615 fastq.gz 4.1 GB
EGAF00004172616 fastq.gz 4.7 GB
EGAF00004172617 fastq.gz 3.5 GB
EGAF00004172618 fastq.gz 3.8 GB
EGAF00004172619 fastq.gz 3.5 GB
EGAF00004172620 fastq.gz 3.9 GB
EGAF00004172621 fastq.gz 3.8 GB
EGAF00004172622 fastq.gz 4.1 GB
EGAF00004172623 fastq.gz 4.2 GB
EGAF00004172624 fastq.gz 4.7 GB
EGAF00004172625 fastq.gz 3.9 GB
EGAF00004172626 fastq.gz 4.7 GB
EGAF00004172627 fastq.gz 3.2 GB
EGAF00004172628 fastq.gz 3.4 GB
EGAF00004172629 fastq.gz 2.4 GB
EGAF00004172630 fastq.gz 2.4 GB
EGAF00004172631 fastq.gz 4.2 GB
EGAF00004172632 fastq.gz 4.5 GB
EGAF00004172633 fastq.gz 3.4 GB
EGAF00004172634 fastq.gz 3.8 GB
EGAF00004172635 fastq.gz 2.9 GB
EGAF00004172636 fastq.gz 3.1 GB
EGAF00004172637 fastq.gz 3.3 GB
EGAF00004172638 fastq.gz 3.5 GB
EGAF00004172639 fastq.gz 3.5 GB
EGAF00004172640 fastq.gz 3.8 GB
EGAF00004172641 fastq.gz 4.9 GB
EGAF00004172642 fastq.gz 4.9 GB
EGAF00004172643 fastq.gz 3.3 GB
EGAF00004172644 fastq.gz 3.8 GB
EGAF00004172645 fastq.gz 3.6 GB
EGAF00004172646 fastq.gz 4.2 GB
EGAF00004172647 fastq.gz 3.7 GB
EGAF00004172648 fastq.gz 4.2 GB
EGAF00004172649 fastq.gz 4.7 GB
EGAF00004172650 fastq.gz 4.8 GB
EGAF00004172651 fastq.gz 3.8 GB
EGAF00004172652 fastq.gz 4.2 GB
EGAF00004172653 fastq.gz 3.3 GB
EGAF00004172654 fastq.gz 3.5 GB
EGAF00004172655 fastq.gz 3.1 GB
EGAF00004172656 fastq.gz 3.3 GB
EGAF00004172657 fastq.gz 1.6 GB
EGAF00004172658 fastq.gz 1.6 GB
EGAF00004172659 fastq.gz 5.6 GB
EGAF00004172660 fastq.gz 5.7 GB
EGAF00004172661 fastq.gz 3.4 GB
EGAF00004172662 fastq.gz 3.5 GB
EGAF00004172663 fastq.gz 2.3 GB
EGAF00004172664 fastq.gz 2.3 GB
EGAF00004172665 fastq.gz 3.1 GB
EGAF00004172666 fastq.gz 3.4 GB
EGAF00004172667 fastq.gz 3.0 GB
EGAF00004172668 fastq.gz 3.2 GB
EGAF00004172669 fastq.gz 4.9 GB
EGAF00004172670 fastq.gz 5.7 GB
EGAF00004172671 fastq.gz 3.4 GB
EGAF00004172672 fastq.gz 3.5 GB
EGAF00004172673 fastq.gz 4.5 GB
EGAF00004172674 fastq.gz 4.9 GB
EGAF00004172675 fastq.gz 2.9 GB
EGAF00004172676 fastq.gz 3.3 GB
EGAF00004172677 fastq.gz 3.2 GB
EGAF00004172678 fastq.gz 3.4 GB
EGAF00004172679 fastq.gz 5.1 GB
EGAF00004172680 fastq.gz 5.4 GB
EGAF00004172681 fastq.gz 3.6 GB
EGAF00004172682 fastq.gz 3.9 GB
EGAF00004172683 fastq.gz 3.3 GB
EGAF00004172684 fastq.gz 3.6 GB
EGAF00004172685 fastq.gz 3.9 GB
EGAF00004172686 fastq.gz 4.5 GB
EGAF00004172687 fastq.gz 3.1 GB
EGAF00004172688 fastq.gz 3.2 GB
EGAF00004172689 fastq.gz 3.5 GB
EGAF00004172690 fastq.gz 3.9 GB
EGAF00004172691 fastq.gz 3.1 GB
EGAF00004172692 fastq.gz 3.4 GB
EGAF00004172693 fastq.gz 2.9 GB
EGAF00004172694 fastq.gz 3.1 GB
EGAF00004172695 fastq.gz 2.9 GB
EGAF00004172696 fastq.gz 3.2 GB
EGAF00004172697 fastq.gz 3.2 GB
EGAF00004172698 fastq.gz 3.4 GB
EGAF00004172699 fastq.gz 2.5 GB
EGAF00004172700 fastq.gz 2.6 GB
EGAF00004172701 fastq.gz 3.6 GB
EGAF00004172702 fastq.gz 3.8 GB
EGAF00004172703 fastq.gz 2.8 GB
EGAF00004172704 fastq.gz 3.0 GB
EGAF00004172705 fastq.gz 2.8 GB
EGAF00004172706 fastq.gz 3.0 GB
EGAF00004172707 fastq.gz 3.3 GB
EGAF00004172708 fastq.gz 3.7 GB
EGAF00004172709 fastq.gz 3.3 GB
EGAF00004172710 fastq.gz 3.6 GB
EGAF00004172711 fastq.gz 2.9 GB
EGAF00004172712 fastq.gz 3.1 GB
EGAF00004172713 fastq.gz 2.9 GB
EGAF00004172714 fastq.gz 3.2 GB
EGAF00004172715 fastq.gz 3.8 GB
EGAF00004172716 fastq.gz 4.3 GB
EGAF00004172717 fastq.gz 3.6 GB
EGAF00004172718 fastq.gz 4.0 GB
EGAF00004172719 fastq.gz 2.1 GB
EGAF00004172720 fastq.gz 2.2 GB
EGAF00004172721 fastq.gz 1.8 GB
EGAF00004172722 fastq.gz 1.8 GB
272 Files (926.2 GB)