Recurrent Amplification of the Osmotic Stress Transcription Factor NFAT5 in Adrenocortical Carcinoma

Author:

Brown Taylor C1ORCID,Nicolson Norman G2ORCID,Man Jianliang2,Gibson Courtney E2,Stenman Adam3ORCID,Juhlin C Christofer34ORCID,Korah Reju2,Carling Tobias2

Affiliation:

1. Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

2. Department of Surgery & Yale Endocrine Neoplasia Laboratory, Yale University School of Medicine, New Haven, Connecticut

3. Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

4. Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden

Abstract

AbstractTumorigenesis requires mitigation of osmotic stress and the transcription factor nuclear factor of activated T cells 5 (NFAT5) coordinates this response by inducing transcellular transport of ions and osmolytes. NFAT5 modulates in vitro behavior in several cancer types, but a potential role of NFAT5 in adrenocortical carcinoma (ACC) has not been studied. A discovery cohort of 28 ACCs was selected for analysis. Coverage depth analysis of whole-exome sequencing reads assessed NFAT5 copy number alterations in 19 ACCs. Quantitative real-time PCR measured NFAT5 mRNA expression levels in 11 ACCs and 23 adrenocortical adenomas. Immunohistochemistry investigated protein expression in representative adrenal samples. The Cancer Genome Atlas database was analyzed to corroborate NFAT5 findings from the discovery cohort and to test whether NFAT5 expression correlated with ion/osmolyte channel and regulatory protein expression patterns in ACC. NFAT5 was amplified in 10 ACCs (52.6%) and clustered in the top 6% of all amplified genes. mRNA expression levels were 5-fold higher compared with adrenocortical adenomas (P < 0.0001) and NFAT5 overexpression had a sensitivity and specificity of 81.8% and 82.7%, respectively, for malignancy. Increased protein expression and nuclear localization occurred in representative ACCs. The Cancer Genome Atlas analysis demonstrated concomitant NFAT5 amplification and overexpression (P < 0.0001) that correlated with increased expression of sodium/myo-inositol transporter SLC5A3 (r2 = 0.237, P < 0.0001) and 14 other regulatory proteins (P < 0.05) previously shown to interact with NFAT5. Amplification and overexpression of NFAT5 and associated osmotic stress response related genes may play an important role adrenocortical tumorigenesis.

Funder

Ohse grant foundation

Publisher

The Endocrine Society

Subject

Endocrinology, Diabetes and Metabolism

Reference41 articles.

1. The characteristics and trends in adrenocortical carcinoma: a United States Population Based Study;Sharma;J Clin Med Res.,2018

2. Adrenocortical carcinoma: current therapeutic state-of-the-art;Lebastchi;J Oncol.,2012

3. Curative resection of adrenocortical carcinoma: rates and patterns of postoperative recurrence;Amini;Ann Surg Oncol.,2016

4. Predictors of survival in adrenocortical carcinoma: an analysis from the national cancer database;Tella;J Clin Endocrinol Metab.,2018

5. Advanced adrenocortical carcinoma - what to do when first-line therapy fails?;Megerle;Exp Clin Endocrinol Diabetes.,2019

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3