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

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.

Breast implant–associated anaplastic large cell lymphoma, a systematic review and in‐depth evaluation of the current understanding

“…Activation of the signal responsive transcription factor 3 (STAT3) is considered the central abnormality in sALCL. Whole genome sequencing of patients with BIA‐ALCL has revealed similar STAT3 overactivation . Activating mutations have also been demonstrated in JAK1 and JAK3 .…”

Breast implant‐associated anaplastic large cell lymphoma and other rare T‐cell lymphomas

“…Rearrangements of the IRF4 / DUSP22 locus at 6p25 and of TP63 , which are frequently observed in systemic or primary cutaneous ALCL, have not been found in any of the cases tested so far (0/46 and 0/37, respectively) . In addition, no structural variants involving the TR genes have been identified …”

“…In a study where TRB deep amplicon sequencing was performed, Variable, Diversity, Joining (VDJ) family usage was not skewed, and analysis of the CDR3 sequences of the dominant clone did not predict affinity for known antigens. Interestingly, the analysis of sequences remaining after substraction of the malignant clone showed a restricted diversity compared with the blood repertoire …”

“…Fewer or no numerical alterations have been identified in the few primary BI‐ALCL samples examined so far, including the primary tumor from which TLR‐1 was derived. In a recent study, Blombery et al reported on genome‐wide copy number variations in 11 effusion‐based BIA‐ALCL samples . This genomic assessment was derived from a hybridation‐based next‐generation sequencing (NGS) study of a large panel of hematologically‐relevant genes.…”

“…So far, a relatively small number of BIA‐ALCL have been successfully analyzed by whole exome or, more commonly, targeted next generation sequencing . The most recurrent finding consists of STAT3 activating mutations found overall in 13/34 cases, with a prevalence ranging from 20% to 64%.…”