Next generation sequencing of breast implant‐associated anaplastic large cell lymphomas reveals a novel STAT3‐JAK2 fusion among other activating genetic alterations within the JAK‐STAT pathway

Abstract

Breast implant associated anaplastic large cell lymphoma (BIA‐ALCL) is a distinct type of ALCL, and a new provisional entity by the 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. In contrast to systemic and primary cutaneous ALCLs, BIA‐ALCLs have been genetically characterized by the absence of fusions and frequent activation of the JAK‐STAT3 pathway through mutations in JAK1 and STAT3. In this study, we report the results of the genetic profiling of 9 BIA‐ALCL cases supporting the role of the JAK‐STAT pathway activation in this entity, including the identification of an activating STAT3‐JAK2 fusion similar to those recently reported in T‐cell lymphoproliferative disorders of the gastrointestinal tract. To our knowledge, this is the first fusion reported in BIA‐ALCL, providing further insight into the overall genetic landscape of this rare entity as well as uncovering potential options for targeted therapy in cases with advanced disease.

ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas

“…The activation of this pathway via STAT3 phosphorylation is almost always present in BIA-ALCL. STAT3 mutations are found in 26% of cases [ 184 , 185 ]. The STAT3 S614R is the predominant point mutation (67%), and it affects the SH2 domain leading to constitutive STAT3 activation and protein phosphorylation [ 182 ].…”

An Update on the Current Genomic Landscape of Breast Implant-Associated Anaplastic Large Cell Lymphoma

“…CREBBP plays a critical role in supporting p53-dependent tumour suppressor functions [ 19 , 20 ]. Quesada et al also demonstrated a high frequency of alteration in epigenetic regulatory pathways, with alteration seen in 56% of patients with TET2, TET3, ARID4B, KDM5C, KDM6A, KMT2C/D and SMARCB1 mutations reported [ 9 ]. Mutations in epigenetic regulators are frequent in T-cell lymphomas and while the contribution epigenetic dysregulation makes in BIA-ALCL lymphogenesis remains unclear, the frequency in which alterations are present may have diagnostic utility.…”

“…Further research is needed to delineate the relative contributions of environmental factors and genetic risk, but it is notable that germline mutations in TP53 have been detected [ 7 , 8 , 9 , 10 ]. Germline TP53 mutations are associated with hereditary cancer syndromes and confer an increased risk to a variety of solid organ malignancies.…”

“…Of note, a STAT3-JAK2 fusion t(17;9)(q21.1) has been reported in one patient who also had TP53 variant. The STAT3-JAK2 fusion has also been seen in T-cell lymphoproliferative disorders of the gastrointestinal tract [ 9 ].…”

“…Recently, the genomic landscape of BIA-ALCL has begun to be characterised, providing insight into the oncogenic mechanisms of a rare and unique entity. Next generation sequencing (NGS) has demonstrated frequent mutations in JAK/STAT activation and signalling pathways, while recurrent mutations in key epigenetic modifiers such as KMT2C and CREBBP have now been reported ( Table 1 ) [ 5 , 7 , 8 , 9 ]. This review aims to summarise the genomic landscape that has been reported to date and current understanding of the molecular aberrancies of BIA-ALCL.…”