Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma

Naoki Oishi; Tanya Hundal; Jessica L Phillips; Surendra Dasari; Guangzhen Hu; David S Viswanatha; Rong He; Ming Mai; Hailey K Jacobs; Nada H Ahmed; Sergei I Syrbu; Youssef Salama; Jennifer R Chapman; Francisco Vega; Jagmohan Sidhu; N Nora Bennani; Alan L Epstein; L Jeffrey Medeiros; Mark W Clemens; Roberto N Miranda; Andrew L Feldman

doi:10.3324/haematol.2019.245860

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Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma

Journal article

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Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma

Naoki Oishi, Tanya Hundal, Jessica L Phillips, Surendra Dasari, Guangzhen Hu, David S Viswanatha, Rong He, Ming Mai, Hailey K Jacobs, Nada H Ahmed, …

Haematologica (Roma), Vol.106(6), pp.1714-1724

05/15/2020

DOI: 10.3324/haematol.2019.245860

PMCID: PMC8168507

PMID: 32414854

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Abstract

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a recently characterized T-cell malignancy that has raised significant patient safety concerns and led to worldwide impact on the implants used and clinical management of patients undergoing reconstructive or cosmetic breast surgery. Molecular signatures distinguishing BIA-ALCL from other ALCLs have not been fully elucidated and classification of BIA-ALCL as a WHO entity remains provisional. We performed RNA sequencing and gene set enrichment analysis comparing BIA-ALCLs to non-BIA-ALCLs and identified dramatic upregulation of hypoxia signaling genes including the hypoxia-associated biomarker CA9 (carbonic anyhydrase-9). Immunohistochemistry validated CA9 expression in all BIA-ALCLs, with only minimal expression in non-BIA-ALCLs. Growth induction in BIA-ALCL-derived cell lines cultured under hypoxic conditions was proportional to up-regulation of CA9 expression, and RNA sequencing demonstrated induction of the same gene signature observed in BIA-ALCL tissue samples compared to non-BIA-ALCLs. CA9 silencing blocked hypoxia-induced BIA-ALCL cell growth and cell cycle-associated gene expression, whereas CA9 overexpression in BIA-ALCL cells promoted growth in a xenograft mouse model. Furthermore, CA9 was secreted into BIA-ALCL cell line supernatants and was markedly elevated in human BIA-ALCL seroma samples. Finally, serum CA9 concentrations in mice bearing BIA-ALCL xenografts were significantly elevated compared to control serum. Together, these findings characterize BIA-ALCL as a hypoxia-associated neoplasm, likely attributable to the unique microenvironment in which it arises. These data support classification of BIA-ALCL as a distinct entity and uncover opportunities for investigating hypoxia-related proteins such as CA9 as novel biomarkers and therapeutic targets in this disease.

anaplastic large cell lymphoma

T-cell lymphoma

breast implant

Details

Title: Subtitle: Molecular profiling reveals a hypoxia signature in breast implant-associated anaplastic large cell lymphoma
Creators: Naoki Oishi - University of Yamanashi
Tanya Hundal - Mayo Clinic
Jessica L Phillips - Mayo Clinic
Surendra Dasari - Mayo Clinic
Guangzhen Hu - Mayo Clinic
David S Viswanatha - Mayo Clinic
Rong He - Mayo Clinic
Ming Mai - Mayo Clinic
Hailey K Jacobs - Mayo Clinic
Nada H Ahmed - Suez Canal University
Sergei I Syrbu - University of Iowa
Youssef Salama - Mayo Clinic
Jennifer R Chapman - University of Miami
Francisco Vega - University of Miami
Jagmohan Sidhu - United Health Services
N Nora Bennani - Mayo Clinic
Alan L Epstein - University of Southern California
L Jeffrey Medeiros - The University of Texas MD Anderson Cancer Center
Mark W Clemens - The University of Texas MD Anderson Cancer Center
Roberto N Miranda - The University of Texas MD Anderson Cancer Center
Andrew L Feldman - Mayo Clinic
Resource Type: Journal article
Publication Details: Haematologica (Roma), Vol.106(6), pp.1714-1724
DOI: 10.3324/haematol.2019.245860
PMID: 32414854
PMCID: PMC8168507
NLM abbreviation: Haematologica
ISSN: 0390-6078
eISSN: 1592-8721
Grant note: R01 CA177734 / NCI NIH HHS P30 CA015083 / NCI NIH HHS P50 CA097274 / NCI NIH HHS
Language: English
Date published: 05/15/2020
Academic Unit: Pathology
Record Identifier: 9984186656602771

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