Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.
Fiche publication
Date publication
novembre 2019
Journal
Blood
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHENARD Marie-Pierre, Dr NICOLAE Alina
Tous les auteurs :
Laurent C, Nicolae A, Laurent C, Le Bras F, Haioun C, Fataccioli V, Amara N, Adélaïde J, Guille A, Schiano JM, Tesson B, Traverse-Glehen A, Chenard MP, Mescam L, Moreau A, Chassagne-Clement C, Somja J, Escudié F, André M, Martin N, Lacroix L, Lemonnier F, Hamy-Petit AS, Reyal F, Bannier M, Oberic L, Prade N, Frénois FX, Beldi-Ferchiou A, Delfau-Larue MH, Bouabdallah R, Birnbaum D, Brousset P, Xerri L, Gaulard P
Lien Pubmed
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, 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 tri-methylation by immunohistochemistry. Twenty cases (59%) showed mutations in at least one member of the JAK/STAT pathway including STAT3 (38%), JAK1 (18%), STAT5B (3%) and in negative regulators like SOCS3 (6%), SOCS1 (3%) and PTPN1 (3%). These mutations were more frequent in tumor-type than in situ samples (p=0.038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in JAK/STAT pathway. Mutations in EOMES gene (12%) involved in lymphocytes 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 JAK/STAT pathway and epigenetic regulators. Our results show that BI-ALCL genomic landscape is not only characterized by JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
Référence
Blood. 2019 Nov 27;: