Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.
Adult
Aged
Aged, 80 and over
Breast Implants
/ adverse effects
DNA Copy Number Variations
Epigenesis, Genetic
Female
Genome, Human
Humans
Janus Kinases
/ metabolism
Lymphoma, Large-Cell, Anaplastic
/ etiology
Middle Aged
Mutation
/ genetics
STAT Transcription Factors
/ metabolism
Signal Transduction
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
30 01 2020
30 01 2020
Historique:
received:
07
06
2019
accepted:
18
11
2019
pubmed:
28
11
2019
medline:
25
6
2020
entrez:
28
11
2019
Statut:
ppublish
Résumé
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
Identifiants
pubmed: 31774495
pii: S0006-4971(20)62276-5
doi: 10.1182/blood.2019001904
pmc: PMC7059458
doi:
Substances chimiques
STAT Transcription Factors
0
Janus Kinases
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
360-370Informations de copyright
© 2020 by The American Society of Hematology.
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