Whole exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas

Abstract

Pheochromocytomas and paragangliomas (PCC/PGL) are the solid tumor 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 tumors. Targeted sequencing of a separate validation set of 103 PCC/PGL identifies somatic ATRX mutations in 12.6% of PCC/PGL. PCC/PGLs with somatic ATRX mutations are associated with alternative lengthening of telomeres and clinically aggressive behavior. This finding suggests that loss of ATRX, a SWI/SNF chromatin remodeling protein, is important in the development of clinically aggressive pheochromocytomas and paragangliomas.