PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors
Ping Chi and colleagues identify recurrent inactivating mutations in the PRC2 core components EED and SUZ12 in malignant peripheral nerve sheath tumors. They further show that PRC2 loss is associated with loss of H3K27 trimethylation and aberrant expression of PRC2 target genes and downstream pathwa...
Saved in:
Published in | Nature genetics Vol. 46; no. 11; pp. 1227 - 1232 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
New York
Nature Publishing Group US
01.11.2014
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | Ping Chi and colleagues identify recurrent inactivating mutations in the PRC2 core components
EED
and
SUZ12
in malignant peripheral nerve sheath tumors. They further show that PRC2 loss is associated with loss of H3K27 trimethylation and aberrant expression of PRC2 target genes and downstream pathways.
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
1
,
2
,
3
. 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. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work |
ISSN: | 1061-4036 1546-1718 |
DOI: | 10.1038/ng.3095 |