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Jan 2020 Blood

Gene alterations in epigenetic modifiers and JAK-STAT signaling are frequent in breast implant-associated ALCL.

Auteurs

Laurent C, Nicolae A, 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, Martin N, Lacroix L, Lemonnier F, Hamy 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

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.

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