Faculty Collaboration Database

Molecular evaluation of a sporadic paraganglioma with concurrent IDH1 and ATRX mutations. Endocrine 2018 Aug;61(2):216-223

Date

05/31/2018

Pubmed ID

29846902

Pubmed Central ID

PMC7461619

DOI

10.1007/s12020-018-1617-1

Scopus ID

2-s2.0-85047840482 (requires institutional sign-in at Scopus site)   7 Citations

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.

Author List

Zhang J, Jiang J, Luo Y, Li X, Lu Z, Liu Y, Huang J, Hou Y, Pang Y, Sun MYF, Wang TS, Evans DB, Pacak K, Zhuang Z, Gao X

Authors

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin
Tracy S. Wang MD, MPH Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adrenal Gland Neoplasms
Aged
DNA Mutational Analysis
Heterozygote
Humans
Isocitrate Dehydrogenase
Male
Mutation
Paraganglioma
X-linked Nuclear Protein