Molecular evaluation of a sporadic paraganglioma with concurrent IDH1 and ATRX mutations
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.
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.
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.
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.
KeywordsParaganglioma IDH1 ATRX Somatic mutations
We thank Dr. Dan Ye from Institute of Biomedical Sciences Fudan University and Dr. Jingmin Yang from Shanghai WeHealth BioMedical Technology Co., Ltd for the technical assistance.
This study was funded by the National Natural Science Foundation of China (Grant number: 81471016) and, in part, by the Intramural Research Program of the NIHNCI, NINDS, and Eunice Kennedy Shriver NICHD.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All the procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration, and its later amendments or comparable ethical standards. The study was approved by the institutional review board of Zhongshan Hospital, Fudan University.
Informed consent was obtained from all individual participants included in the study.
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