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.
Highlights
Pheochromocytomas and paragangliomas (PCC/PGL) are the solid tumour type most commonly associated with an inherited susceptibility syndrome
This relatively low number of mutations in PCC/PGL is consistent with that seen in related tumour types, such as neuroblastomas (B12–18/tumour) and pancreatic neuroendocrine tumours (PNETs; B16/tumour)[20,21]
Germline mutations lead to X-linked alpha thalassemia mental retardation syndrome; somatic mutations are implicated as drivers in several nonepithelial cancer types including PNETs, neuroblastomas and gliomas[20,21,25,26,30]
Summary
Pheochromocytomas and paragangliomas (PCC/PGL) are the solid tumour type most commonly associated with an inherited susceptibility syndrome. 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. One-fourth of patients with PCC/PGL have malignant disease defined by the presence of distant metastases[15], and when metastatic, PCC/PGL are associated with a 50% 5-year survival rate[16]. No reliable predictors of aggressive disease exist other than a germline mutation in the Succinate dehydrogenase (SDH) B gene, which confers a higher risk of malignancy (31–75%) than mutations in other susceptibility genes (usually o5%)[18]. We aim to identify driver mutations for clinically aggressive PCC/PGL by performing whole-exome sequencing (WES) on a discovery set of 21 fresh-frozen tumour/matched germline DNA samples. We are the first to report ATRX mutations in PCC/PGL and suggest that ATRX loss is important for tumorigenesis in a subset of PCC/PGL
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