Frequent activating STAT3 mutations and novel recurrent genomic abnormalities detected in breast implant-associated anaplastic large cell lymphoma

Abstract

// Piers Blombery 1, 2 , Ella Thompson 1, 2 , Georgina L. Ryland 1 , Rachel Joyce 3, 4 , David J. Byrne 1 , Christine Khoo 1 , Stephen Lade 1 , Mark Hertzberg 5 , Greg Hapgood 6 , Paula Marlton 6 , Anand Deva 7 , Geoffrey Lindeman 1, 3, 8 , Stephen Fox 1, 2 , David Westerman 1, 2 and Miles Prince 1, 2 1 Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia 2 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia 3 Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia 4 Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia 5 Department of Haematology, Prince of Wales Hospital, University of New South Wales, Randwick, NSW, Australia 6 Department of Haematology, Princess Alexandra Hospital, Brisbane, QLD, Australia 7 Surgical Infection Research Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia 8 Department of Medicine, The University of Melbourne, Parkville, VIC, Australia Correspondence to: Piers Blombery, email: Piers.blombery@petermac.org Keywords: lymphoma; genomics; NGS Received: July 29, 2018      Accepted: October 25, 2018      Published: November 16, 2018 ABSTRACT Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell lymphoma that occurs after implantation of breast prostheses. We performed comprehensive next generation sequencing based genomic characterization of 11 cases of BIA-ALCL including sequence variant detection on 180 genes frequently mutated in haematological malignancy, genome-wide copy number assessment, structural variant detection involving the T-cell receptor loci and TRB deep-sequencing. We observed sequence variants leading to JAK/STAT activation in 10 out of 11 patients. We also observed germline TP53 mutations in two cases. In addition we detected a recurrent copy number loss involving RPL5 as well as copy number amplifications involving TNFRSF11A [RANK] (in 2 cases), MYC , P2RX7 , TMEM119 and PDGFRA . In summary, our comprehensive genomic characterisation of 11 cases of BIA-ALCL has provided insight into potential pathobiological mechanisms (JAK/STAT, MYC and TP53) as well as identifying targets for future therapeutic intervention (TNFRSF11A, PDGFRA) in this rare entity.