Loss of Expression of Atrx and Daxx in Pheochromocytomas and Paragangliomas

Presentation Number: MON 400
Date of Presentation: April 3rd, 2017

Philip Göstasson*1, Samuel Backman2, Per Hellman2 and Peyman Bjorklund2
1Uppsala University, 2Uppsala University, Sweden

Abstract

Introduction

Phaeochromocytomas and paragangliomas (PPGLs) are rare tumors originating from chromaffin cells in the adrenal medulla or sympathetic ganglia, respectively. Approximately 40% of PPGLs are associated with germline mutations. The genes ATRX and DAXX encode transcriptional regulator ATRX and death domain-associated protein 6, respectively, involved in the chromatin remodeling pathway. Whole exome sequencing has identified somatic, inactivating ATRX mutations in PPGLs at a rate of 12.6%, being associated with alternative lengthening of telomeres and a clinically more aggressive behavior. The mutations were associated with a lack of nuclear expression of transcriptional regulator ATRX, investigated by immunohistochemistry. The aim of this study was to analyze the clinical impact of nuclear expression of transcriptional regulator ATRX and death domain-associated protein 6 in PPGLs.

Methods

Frozen sections from 85 PPGLs (74 patients; 28 males, 46 females) were subjected to immunohistochemical staining for transcriptional regulator ATRX and death domain-associated protein 6 and subsequently classified as either negative or positive. Patients with at least one negative tumor were classified as negative. Overall survival (OS; months), disease-free survival (DFS; months), size of primary tumor and age at time of diagnosis were collected from medical records.

Results

Tumors from 22 of the 74 patients were classified as negative in either transcriptional regulator ATRX or death domain-associated protein 6 nuclear expression. Patients with positive tumors had a significantly lower age at time of diagnosis (54,5 vs 45 years; p=0,0196). There were no significant differences regarding the other investigated clinical parameters.

Conclusion

The significantly lower age at time of diagnosis in patients with tumors expressing transcriptional regulator ATRX and death domain-associated protein 6 may indicate a more rapid progression of tumorigenesis, and motivates further investigation to elucidate the clinical impact of ATRX and DAXX mutations in PPGLs.

 

Nothing to Disclose: PG, SB, PH, PB