Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas and paragangliomas (PCC/PGL) are the solid tumour type most commonly associated with an inherited susceptibility syndrome. However, very little is known about the somatic genetic changes leading to tumorigenesis or malignant transformation. Here we perform whole-exome sequencing on a discovery set of 21 PCC/PGL and identify somatic ATRX mutations in two SDHB-associated tumours. Targeted sequencing of a separate validation set of 103 PCC/PGL identifies somatic ATRX mutations in 12.6% of PCC/PGL. PCC/PGL with somatic ATRX mutations are associated with alternative lengthening of telomeres and clinically aggressive behaviour. This finding suggests that loss of ATRX, an SWI/SNF chromatin remodelling protein, is important in the development of clinically aggressive PCC/PGL.

Figure 1. Immunohistochemistry and immunofluorescence in PCC/PGL with somatic ATRX mutations

FFPE tumor PP119Z1 shows absence of ATRX in tumor cells (arrow; panel A) with the presence in endothelial cells (arrow head) as an internal control; DAXX staining was positive (panel B). Telomere FISH shows alternative lengthening of telomeres in two SDHB-associated PCC/PGLs with somatic ATRX mutations from the discovery and validation sets, PP119Z1 (panel C) and PP142Z1 (panel D), respectively. Scale bars, 30 µm.