Format

Send to

Choose Destination
Endocrine. 2018 Aug;61(2):216-223. doi: 10.1007/s12020-018-1617-1. Epub 2018 May 30.

Molecular evaluation of a sporadic paraganglioma with concurrent IDH1 and ATRX mutations.

Author information

1
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
2
Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China.
3
Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
4
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
5
Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
6
College of Liberal Arts and Sciences, University of Illinois at Chicago, Chicago, IL, USA.
7
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA.
8
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
9
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China. gao.xin@zs-hospital.sh.cn.
10
Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China. gao.xin@zs-hospital.sh.cn.

Abstract

PURPOSE:

Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of neural crest origin. Germline or somatic mutations of numerous genes have been implicated in the pathogenesis of PPGLs, including the isocitrate dehydrogenase 1 (IDH1) gene and alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene. Although concurrent IDH1 and ATRX mutations are frequently seen in gliomas, they have never been reported together in PPGLs. The aim of this study was to characterize one paraganglioma with concurrent IDH1 and ATRX mutations identified by whole exome sequencing.

METHODS:

Leukocyte and tumor DNA were used for whole exome sequencing and Sanger sequencing. 2-hydroxyglurarate level and the global DNA methylation status in the tumor were measured. ATRX's cDNA transcripts were analyzed. Tyrosine hydroxylase (TH), HIF1α and ATRX staining, as well as telomere-specific FISH was also performed.

RESULTS:

The presence of a somatic IDH1 (c.394C>T, p.R132C) mutation and a concurrent somatic ATRX splicing mutation (c.4318-2A>G) in the current case was confirmed. Dramatic accumulation of 2-hydroxyglutarate was detected in the paraganglioma without the global DNA hypermethylation, and pseudohypoxia was also activated. Importantly, immunohistochemistry revealed negative TH staining in the tumor and the first exon region of TH gene was hypermethylated resulting in normal plasma metanephrines. The splicing ATRX mutation resulted in two transcripts, causing frameshifts. Immunohistochemistry revealed scarce ATRX staining in the tumor. Alternative lengthening of telomeres (ALT) was detected by FISH.

CONCLUSIONS:

This case represents the first concurrence of IDH1 and ATRX mutations in PPGLs. Although relatively rare, a somatic R132C mutation of IDH1 might play a role in a small subset of sporadic PPGLs.

KEYWORDS:

ATRX; IDH1; Paraganglioma; Somatic mutations

PMID:
29846902
DOI:
10.1007/s12020-018-1617-1

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center