Abstract 3892: Somatic genetic profiling in pheochromocytomas and paragangliomas
Authors: Fishbein Lauren , Khare Sanika , Wubbenhorst Bradley , LiVolsi Virginia , Montone Kathleen , Fraker Douglas , Cohen Debbie L. , Nathanson Katherine L. 
Published: August 2015

Abstract
Approximately one quarter of pheochromocytomas and paragangliomas (PCC/PGLs) are malignant, defined as having distant metastases, which can be present at initial diagnosis or develop even 20 years later. Patients with malignant PCC/PGL only have a 50% five year survival rate. This poor prognosis and potential long latency period emphasizes the need for biomarkers of aggressive disease and novel targets for therapeutic intervention. More than eleven known susceptibility genes have been identified. Nevertheless, very little is known about the activated cellular pathways or the somatic genetic and genomic changes leading to tumor development and progression to malignancy. We aimed to characterize the somatic genetic profile in clinically benign and clinically aggressive PCC/PGLs in order to identify alterations leading to tumorigenesis and malignant potential. We performed exome sequencing on matched germline and tumor DNA from 21 PCC/PGLs including five VHL-associated PCCs representing clinically benign disease, seven SDHB-associated PCC/PGLs representing clinically aggressive disease, and two SDHD-associated and seven sporadic PCC/PGLs representing a mix of clinical behavior. Three hundred and twenty-one protein altering variants were identified. There were seven truncating mutations (nonsense variants and frameshifts) and twelve variants affecting splice sites. The vast majority of variants were non-synonymous variants of undetermined significance. Three of the seven sporadic tumors had somatic NF1 mutations, but no somatic mutations in any of the other known susceptibility genes were observed. In addition to somatic ATRX mutations which we have previously reported, there were a number of cancer associated genes with somatic variants including SHH, FANCD2, CTNND1, MACC1, FGFR1, GADD45A, and RBBP6. Pathway analysis identified a broad range of disrupted pathways including the WNT and cadherin signaling pathways. For tumors with a known inherited mutations in VHL or SDHx, copy number variation analysis identified loss of heterozygosity as the second hit. In summary, we performed a comprehensive somatic exome sequencing analysis of a large set of PCC/PGLs, and we identified several cancer associated genes not previously reported to be altered in PCC/PGLs. These data not only expand upon the limited prior knowledge of somatic alterations in PCC/PGLs but may also serve to identify potential targets for therapeutic intervention.
Citation Format: Lauren Fishbein, Sanika Khare, Bradley Wubbenhorst, Virginia LiVolsi, Kathleen Montone, Douglas Fraker, Debbie L. Cohen, Katherine L. Nathanson. Somatic genetic profiling in pheochromocytomas and paragangliomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3892. doi:10.1158/1538-7445.AM2015-3892