Journal article
Abstract 6084: Recurrent genomic patterns of MPNST evolution correlate with clinical outcome
Cancer research (Chicago, Ill.), v 82(12_Supplement), pp 6084-6084
15 Jun 2022
Abstract
Abstract Neurofibromatosis type 1 (NF1) is the most common tumor predisposition syndrome, and is associated with an aggressive soft-tissue sarcoma, malignant peripheral nerve sheath tumours (MPNSTs), the greatest cause of mortality in people with NF1. The only potentially curative therapy involves en bloc resection with negative margins, which is not always appropriate. Even therapy with curative intent is associated with poor overall survival for both sporadic and NF1-related MPNSTs. The development of novel therapies has been largely hindered by a poor understanding of the molecular events underpinning MPNST pathogenesis. We report a comprehensive multi-omic study of MPNST evolution based on whole genome sequencing, transcriptomic and methylation profiling data on 95 tumors (64 NF1-related; 31 sporadic). In all cases, the early events in MPNST evolution involve biallelic inactivation of NF1 followed by inactivation of CDKN2A, as well as mutations in TP53 or PRC2 complex genes in a subset of cases. Analysis of the genomic architecture revealed distinct pathways of tumor evolution that can be identified through H3K27 trimethylation (H3K27me3) status. Integration of these data allows us to propose several mechanistic tumor evolution models. Tumors with H3K27me3 loss evolve through extensive copy number aberrations (CNAs) including haploidization followed by whole genome doubling and chromosome 8 amplifications, whereas tumors with H3K27me3 retention evolve through extensive chromosome instability and chromothripsis. Taken together, these genome-wide CNA profiles act as a surrogate for the loss of H3K27me3 status and correlate with prognosis, suggesting that CNA profiling of cell-free DNA could be incorporated in clinical decision-making. Citation Format: Isidro Cortes Ciriano, Chris D. Steele, Katherine Piculell, Alyaa Al-Ibraheemi, Vanessa Eulo, Marilyn M. Bui, Aikaterini Chatzipli, Brendan C. Dickson, Dana C. Borcherding, Alon Galor, Jesse Hart, Andrew Feber, Kevin B. Jones, Justin T. Jordan, Raymond H. Kim, Daniel Lindsay, Colin Miller, Yoshihiro Nishida, Jonathan Serrano, Nicole J. Ullrich, David Viskochil, Xia Wang, Matija Snuderl, Paula Proszek, Peter J. Park, Adrienne M. Flanagan, Angela C. Hirbe, Nischalan Pillay, David T. Miller, The Genomics of MPNST (GeM) Consortium. Recurrent genomic patterns of MPNST evolution correlate with clinical outcome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6084.
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Details
- Title
- Abstract 6084: Recurrent genomic patterns of MPNST evolution correlate with clinical outcome
- Creators
- Isidro Cortes Ciriano - 1European Molecular Biology Laboratory, Cambridge, United Kingdom;Chris D. Steele - London CancerKatherine Piculell - Boston Children's HospitalAlyaa Al-Ibraheemi - Boston Children's HospitalVanessa Eulo - University of Alabama at BirminghamMarilyn M. Bui - Moffitt Cancer CenterAikaterini Chatzipli - 6Harvard Medical School, Boston, MA;Brendan C. Dickson - University of TorontoDana C. Borcherding - Washington University in St. LouisAlon Galor - University of OxfordJesse Hart - Providence CollegeAndrew Feber - Royal Marsden NHS Foundation TrustKevin B. Jones - Huntsman Cancer InstituteJustin T. Jordan - Massachusetts General HospitalRaymond H. Kim - University of TorontoDaniel Lindsay - Royal National Orthopaedic HospitalColin Miller - European Bioinformatics InstituteYoshihiro Nishida - Nagoya University HospitalJonathan Serrano - New York UniversityNicole J. Ullrich - Boston Children's HospitalDavid Viskochil - Huntsman Cancer InstituteXia Wang - Moffitt Cancer CenterMatija Snuderl - New York UniversityPaula Proszek - Royal Marsden NHS Foundation TrustPeter J. Park - 6Harvard Medical School, Boston, MA;Adrienne M. Flanagan - London CancerAngela C. Hirbe - Washington University in St. LouisNischalan Pillay - London CancerDavid T. Miller - Boston Children's HospitalThe Genomics of MPNST (GeM) ConsortiumLindsay A Steele - School of Biomedical Engineering, Science, and Health Systems (1997-)
- Publication Details
- Cancer research (Chicago, Ill.), v 82(12_Supplement), pp 6084-6084
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems; Drexel University
- Other Identifier
- 991019356497704721