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JAK-STAT PATHWAY AND EPIGENETIC REGULATORS ARE CRITICAL PLAYERS IN BI-ALCL PATHOGENESIS?
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International audience. Background: Breast Implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma arising in association with breast implant, particularly those with textured surfaces. We recently identified two histopathological BI-ALCL subtypes: in-situ and tumor-type which correlated with the seroma vs tumor mass clinical presentation, respectively. Although genetic events involving the JAK/STAT pathway have been reported and the putative role of local chronic inflammation has been suspected, BI-ALCL pathogenesis remains elusive. To further explore potential molecular mechanisms involved in the pathobiology of these two distinct BI-ALCL subtypes, we performed a genomic characterization of 34 such cases. Patient and Methods: Fifty-four BI-ALCL patients have been diagnosedthrough the Lymphopath network and registered in the Lymphoma Study Association Registry from 2010 to 2018. A total of 34 BI-ALCL samples have been analyzed by whole exome sequencing (WES) (n = 22 paired tumor/ germline DNA) and/or targeted next generation sequencing (NGS) (n = 24), across 406 genes to validate the findings. The average depth of sequencing was 300x for WES and 500x for targeted NGS. Results: Fifty nine percent of cases (20/34) showed mutations in at least one member of the JAK/STAT signaling pathway. STAT3(38%)and JAK1 (18%) were the most mutated genes whereas STAT5B (n = 1) and the negative regulators SOCS3 (n = 2), SOCS1 (n = 1) andPTPN1 (n = 1) were seldom mutated. Fifteen percent of cases harbored simultaneous mutations in two genes of this pathway. STAT3mutations were more frequent in tumor-type than in-situ BI-ALCL (p = 0.0078). Recurrent mutations in epigenetic modifiers were seenin 70% of cases with KMT2C (26%), CHD2 (15%), CREBBP (15%) and KMT2D (9%) being the most frequently mutated genes. Loss of function mutations in TP53 (12%) have also been identified. Genomic alterations in genes involved in lymphocytes development such as EOMES and in PI3K-AKT and MAP cascades were also seen in 23.5%, 12% and 9% BI-ALCL cases, respectively. In addition, CNV analysis in 8 cases identified recurrent deletions on chromosomes 8q, 15p and 20. Furthermore, by this approach additional alterations in SOCS3 (2/8), SOCS1 (1/8), PTPN1 (6/8) and STAT5B (3/8) as well as LOH in several epigenetic regulators such as TET2 (3/8) and HDAC8 (2/8) were seen.Conclusions: This large series strongly reinforce the hypothesis that dysregulation of cytokine receptor signaling caused by recurrentmutations in the JAK/STAT pathway is a key event in BI-ALCL pathogenesis. Furthermore, our observation of frequent mutations in chro-matin remodeling genes highlights the importance of epigenome and provides new insights into the complexity of BI-ALCL oncogenesis.Keywords: anaplastic large cell lymphoma (ALCL); epigenetics; JAK/STAT.
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