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PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors
William Lee1, Sewit Teckie2, Thomas Wiesner3
11] Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA. [2] Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Abstract:
Malignant peripheral nerve sheath tumors (MPNSTs) represent a group of highly aggressive soft-tissue sarcomas that may occur sporadically, in association with neurofibromatosis type I (NF1 associated) or after radiotherapy. Using comprehensive genomic approaches, we identified loss-of-function somatic alterations of the Polycomb repressive complex 2 (PRC2) components (EED or SUZ12) in 92% of sporadic, 70% of NF1-associated and 90% of radiotherapy-associated MPNSTs. MPNSTs with PRC2 loss showed complete loss of trimethylation at lysine 27 of histone H3 (H3K27me3) and aberrant transcriptional activation of multiple PRC2-repressed homeobox master regulators and their regulated developmental pathways. Introduction of the lost PRC2 component in a PRC2-deficient MPNST cell line restored H3K27me3 levels and decreased cell growth. Additionally, we identified frequent somatic alterations of CDKN2A (81% of all MPNSTs) and NF1 (72% of non-NF1-associated MPNSTs), both of which significantly co-occur with PRC2 alterations. The highly recurrent and specific inactivation of PRC2 components, NF1 and CDKN2A highlights their critical and potentially cooperative roles in MPNST pathogenesis.
Insights
Loss-of-function alterations in Polycomb repressive complex 2 (PRC2) are common in malignant peripheral nerve sheath tumors (MPNSTs). Inactivation of PRC2, NF1, and CDKN2A are critical in MPNST development.
Area of Science:
- Oncology
- Genetics
- Epigenetics
Background:
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas with diverse origins.
- MPNSTs can arise sporadically, be associated with neurofibromatosis type I (NF1), or develop after radiotherapy.
- Understanding the genetic underpinnings of MPNSTs is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the comprehensive genomic landscape of MPNSTs.
- To identify key genetic alterations driving MPNST pathogenesis.
- To explore the cooperative roles of identified genes in MPNST development.
Main Methods:
- Comprehensive genomic profiling of MPNST samples.
- Analysis of somatic alterations in Polycomb repressive complex 2 (PRC2) components (EED, SUZ12).
- Assessment of alterations in CDKN2A and NF1 genes and their co-occurrence with PRC2 alterations.
Main Results:
- Loss-of-function somatic alterations in PRC2 components (EED or SUZ12) were identified in a high percentage of sporadic (92%), NF1-associated (70%), and radiotherapy-associated (90%) MPNSTs.
- PRC2 loss led to decreased H3K27me3 levels and aberrant activation of homeobox genes.
- Frequent somatic alterations in CDKN2A (81%) and NF1 (72%) were observed and significantly co-occurred with PRC2 alterations.
Conclusions:
- Inactivation of PRC2 components is a highly recurrent event in MPNST pathogenesis across different etiological subtypes.
- The study highlights the critical and potentially cooperative roles of PRC2, NF1, and CDKN2A in MPNST development.
- Restoring PRC2 function in deficient cells reduced tumor cell growth, suggesting therapeutic potential.
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