Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
01 03 2023
01 03 2023
Historique:
received:
19
07
2022
revised:
09
11
2022
accepted:
16
12
2022
pubmed:
5
1
2023
medline:
3
3
2023
entrez:
4
1
2023
Statut:
ppublish
Résumé
Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.
Identifiants
pubmed: 36598417
pii: 716761
doi: 10.1158/2159-8290.CD-22-0786
pmc: PMC9983734
mid: NIHMS1861188
doi:
Substances chimiques
Histones
0
Biomarkers, Tumor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
654-671Subventions
Organisme : Intramural NIH HHS
ID : Z99 CA999999
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA BC011722
Pays : United States
Informations de copyright
©2023 The Authors; Published by the American Association for Cancer Research.
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