{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T16:36:45Z","timestamp":1792427805421,"version":"4.5.0"},"reference-count":31,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T00:00:00Z","timestamp":1585785600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The Genomics of Malignant Peripheral Nerve Sheath Tumor (GeM) Consortium is an international collaboration focusing on multi-omic analysis of malignant peripheral nerve sheath tumors (MPNSTs), the most aggressive tumor associated with neurofibromatosis type 1 (NF1). Here we present a summary of current knowledge gaps, a description of our consortium and the cohort we have assembled, and an overview of our plans for multi-omic analysis of these tumors. We propose that our analysis will lead to a better understanding of the order and timing of genetic events related to MPNST initiation and progression. Our ten institutions have assembled 96 fresh frozen NF1-related (63%) and sporadic MPNST specimens from 86 subjects with corresponding clinical and pathological data. Clinical data have been collected as part of the International MPNST Registry. We will characterize these tumors with bulk whole genome sequencing, RNAseq, and DNA methylation profiling. In addition, we will perform multiregional analysis and temporal sampling, with the same methodologies, on a subset of nine subjects with NF1-related MPNSTs to assess tumor heterogeneity and cancer evolution. Subsequent multi-omic analyses of additional archival specimens will include deep exome sequencing (500\u00d7) and high density copy number arrays for both validation of results based on fresh frozen tumors, and to assess further tumor heterogeneity and evolution. Digital pathology images are being collected in a cloud-based platform for consensus review. The result of these efforts will be the largest MPNST multi-omic dataset with correlated clinical and pathological information ever assembled.<\/jats:p>","DOI":"10.3390\/genes11040387","type":"journal-article","created":{"date-parts":[[2020,4,2]],"date-time":"2020-04-02T13:39:34Z","timestamp":1585834774000},"page":"387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Genomics of MPNST (GeM) Consortium: Rationale and Study Design for Multi-Omic Characterization of NF1-Associated and Sporadic MPNSTs"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1060-1945","authenticated-orcid":false,"given":"David T.","family":"Miller","sequence":"first","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-494X","authenticated-orcid":false,"given":"Isidro","family":"Cort\u00e9s-Ciriano","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge CB10 1SD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nischalan","family":"Pillay","sequence":"additional","affiliation":[{"name":"Department of Pathology, University College London Cancer Institute, Bloomsbury, London WC1E 6BT, UK"},{"name":"Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1719-0771","authenticated-orcid":false,"given":"Angela C.","family":"Hirbe","sequence":"additional","affiliation":[{"name":"Oncology Division, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matija","family":"Snuderl","sequence":"additional","affiliation":[{"name":"Department of Pathology, New York University Langone Health, New York City, NY 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn M.","family":"Bui","sequence":"additional","affiliation":[{"name":"Department of Pathology, Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Piculell","sequence":"additional","affiliation":[{"name":"Division of Genetics and Genomics, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyaa","family":"Al-Ibraheemi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2269-6216","authenticated-orcid":false,"given":"Brendan C.","family":"Dickson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Mt. Sinai Hospital, Toronto, ON M5G 1XF, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesse","family":"Hart","sequence":"additional","affiliation":[{"name":"Department of Pathology, Lifespan Laboratories, Rhode Island Hospital, Providence, RI 02903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Jones","sequence":"additional","affiliation":[{"name":"Departments of Orthopaedics and Oncological Sciences; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin T.","family":"Jordan","sequence":"additional","affiliation":[{"name":"Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2147-8674","authenticated-orcid":false,"given":"Raymond H.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 2C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Lindsay","sequence":"additional","affiliation":[{"name":"Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Nishida","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation, Nagoya University Hospital, Nagoya 466-8550, Aichi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole J.","family":"Ullrich","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"GeneHome, Moffitt Cancer Center, Tampa, FL 33612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne M.","family":"Flanagan","sequence":"additional","affiliation":[{"name":"Department of Pathology, University College London Cancer Institute, Bloomsbury, London WC1E 6BT, UK"},{"name":"Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/2045-3329-2-17","article-title":"Malignant peripheral nerve sheath tumours in inherited disease","volume":"2","author":"Evans","year":"2012","journal-title":"Clin. Sarcoma Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"142","DOI":"10.3171\/2012.9.JNS101610","article-title":"Role of resection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1","volume":"118","author":"Dunn","year":"2013","journal-title":"J. Neurosurg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1002\/1097-0142(19900915)66:6<1253::AID-CNCR2820660627>3.0.CO;2-R","article-title":"Malignant peripheral nerve sheath tumors of the buttock and lower extremity. A study of 43 cases","volume":"66","author":"Hruban","year":"1990","journal-title":"Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1200\/JCO.2001.19.5.1238","article-title":"Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial","volume":"19","author":"Frustaci","year":"2001","journal-title":"J. Clin. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.suc.2008.03.005","article-title":"The role of radiation therapy in the management of sarcomas","volume":"88","author":"Kaushal","year":"2008","journal-title":"Surg. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1200\/JCO.1998.16.1.197","article-title":"Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity","volume":"16","author":"Yang","year":"1998","journal-title":"J. Clin. Oncol."},{"key":"ref_7","first-page":"1573","article-title":"International consensus statement on malignant peripheral nerve sheath tumors in neurofibromatosis","volume":"62","author":"Ferner","year":"2002","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Prudner, B.C., Ball, T., Rathore, R., and Hirbe, A.C. (2019). Diagnosis and management of malignant peripheral nerve sheath tumors: Current practice and future perspectives. Neuro Oncol. Adv.","DOI":"10.1093\/noajnl\/vdz047"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7429697","DOI":"10.1155\/2017\/7429697","article-title":"Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies","volume":"2017","author":"Kim","year":"2017","journal-title":"Sarcoma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1038\/ng.3095","article-title":"PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors","volume":"46","author":"Lee","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1038\/ng.3116","article-title":"Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors","volume":"46","author":"Zhang","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Pemov, A., Li, H., Presley, W., Wallace, M.R., and Miller, D.T. (2019). Genetics of human malignant peripheral nerve sheath tumors. Neuro Oncol. Adv.","DOI":"10.1093\/noajnl\/vdz049"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s00401-016-1540-6","article-title":"Methylation-based classification of benign and malignant peripheral nerve sheath tumors","volume":"131","author":"Rohrich","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1093\/neuonc\/nou140","article-title":"Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis","volume":"17","author":"Danielsen","year":"2015","journal-title":"Neuro Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3168","DOI":"10.1038\/onc.2016.464","article-title":"The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas","volume":"36","author":"Pemov","year":"2017","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1086\/302747","article-title":"Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1","volume":"66","author":"Eisenbarth","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.ajpath.2015.10.023","article-title":"The Challenge of Cancer Genomics in Rare Nervous System Neoplasms: Malignant Peripheral Nerve Sheath Tumors as a Paradigm for Cross-Species Comparative Oncogenomics","volume":"186","author":"Carroll","year":"2016","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/nature13561","article-title":"PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies","volume":"514","author":"Beert","year":"2014","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.ccell.2018.01.005","article-title":"Programming of Schwann Cells by Lats1\/2-TAZ\/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis","volume":"33","author":"Wu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41576-019-0114-6","article-title":"Resolving genetic heterogeneity in cancer","volume":"20","author":"Turajlic","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_21","first-page":"64","article-title":"WHO classification of tumours of soft tissue and bone 2013: The main changes compared to the 3rd edition","volume":"50","author":"Zambo","year":"2014","journal-title":"Cesk. Patol."},{"key":"ref_22","unstructured":"Cancer Genome Atlas Research Network (2017). Electronic address, E.D.S.C.; Cancer Genome Atlas Research, N. Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. Cell, 171, 950\u2013965."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"15180","DOI":"10.1038\/ncomms15180","article-title":"A molecular portrait of microsatellite instability across multiple cancers","volume":"8","author":"Lee","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1126\/science.aag0299","article-title":"Mutational signatures associated with tobacco smoking in human cancer","volume":"354","author":"Alexandrov","year":"2016","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1038\/s41588-018-0179-8","article-title":"Copy number signatures and mutational processes in ovarian carcinoma","volume":"50","author":"Macintyre","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.ccell.2019.02.002","article-title":"Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways","volume":"35","author":"Steele","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Davoli, T., Uno, H., Wooten, E.C., and Elledge, S.J. (2017). Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Science, 355.","DOI":"10.1126\/science.aaf8399"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8940","DOI":"10.1038\/ncomms9940","article-title":"Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency","volume":"6","author":"Kovac","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"AACR Project GENIE Consortium (2017). AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov., 7, 818\u2013831.","DOI":"10.1158\/2159-8290.CD-17-0151"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/4\/387\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:14:47Z","timestamp":1760174087000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/11\/4\/387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,2]]},"references-count":31,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["genes11040387"],"URL":"https:\/\/doi.org\/10.3390\/genes11040387","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,2]]}}}