Abstract 4371: Integrated molecular characterization of pheochromocytoma and paraganglioma including a novel, recurrent and prognostic fusion gene
Authors: Fishbein Lauren , Leshchiner Ignaty , Walter Vonn , Danilova Ludmila , Robertson A Gordon , Johnson Amy , Lichtenberg Tara , Murray Bradley A. , Ghayee Hanse K. , Else Tobias , Ling Shiyun , Jefferys Stuart R. , de Cubas Aguirre A. , Wenz Brandon , Korpershoek Esther , Amelio Antonio L. , Makowski Liza , Rathmell W Kimryn , Gimenez-Roqueplo Anne-Paule , Giordano Thomas J. , Asa Sylvia L. , Tischler Arthur S. ,   The Cancer Genome Atlas Pheochromocytoma and Paraganglioma Analysis Working Group, Pacak Karel , Nathanson Katherine L. , Wilkerson Matthew D. 
Published: July 2016

Abstract
Pheochromocytomas (PCC) and paragangliomas (PGL) are tumors of the autonomic nervous system; 25% are metastatic or locally aggressive. Characterization of the inherited basis of disease has identified a variety of underlying germline mutations; however, understanding of somatic alterations remains limited. As part of The Cancer Genome Atlas, we performed the most comprehensive genomic characterization of PCC/PGL to date, by applying eight genomic profiling assays to 173 patients. Despite having a low overall mutation rate per tumor, we observed remarkable diversity in genomic alterations. 27% of patients had a pathogenic germline mutation among eight known familial PCC/PGL susceptibility genes, thus making PCC/PGL the tumor type with the greatest rate of germline mutations in The Cancer Genome Atlas. 38% of patients possessed a somatic driver mutation across 12 genes. RET, NF1 and VHL were affected by both germline and somatic mutation, albeit with different mutation site tendencies. We identified a new somatic driver gene, CSDE1, which had coordinated intron splicing defects, DNA copy number loss, and RNA under-expression, suggesting a loss of function consequence. Most notably, we discovered the first fusion genes in PCC/PGL from RNA and DNA sequencing (7% of patients), demonstrating for the first time that inter-chromosomal translocation and gene fusion is a method of molecular pathogenesis in this disease. Recurrent, novel MAML3 fusion genes spanned three isoforms and were activating based on over-expression of MAML3 and on fusion transcript exonic expression. MAML3 fusion positive tumors had concomitant dual focal DNA amplification of the fusion gene partners and a significantly divergent methylation profile. Another novel driver gene in PCC/PGL, BRAF, was affected by a hotspot somatic mutation and by an activating fusion gene. Through integrated platform analysis, four statistically significant molecular subtypes of PCC/PGL were detected and found to represent divergent molecular etiology – the kinase signaling subtype, the pseudohypoxia subtype, the Wnt-altered subtype, and the cortical admixture subtype. In particular, MAML3 fusions and CSDE1 mutations defined the new Wnt-altered expression subtype of PCC. Adding to the limited set of prognostic markers in PCC/PGL, three molecular markers were positively associated with clinically aggressive disease: germline mutations in SDHB, somatic mutations in ATRX and fusions involving MAML3. Nearly all somatic driver mutations, germline driver mutations and fusion genes were mutually exclusive across the cohort and covered a large portion of the cohort (69%). Our study provides important novel insights into PCC/PGL biology and identifies potential markers for aggressive disease and therapeutic intervention.
Citation Format: Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A Gordon Robertson, Amy Johnson, Tara Lichtenberg, Bradley A. Murray, Hanse K. Ghayee, Tobias Else, Shiyun Ling, Stuart R. Jefferys, Aguirre A. de Cubas, Brandon Wenz, Esther Korpershoek, Antonio L. Amelio, Liza Makowski, W Kimryn Rathmell, Anne-Paule Gimenez-Roqueplo, Thomas J. Giordano, Sylvia L. Asa, Arthur S. Tischler, The Cancer Genome Atlas Pheochromocytoma and Paraganglioma Analysis Working Group, Karel Pacak, Katherine L. Nathanson, Matthew D. Wilkerson. Integrated molecular characterization of pheochromocytoma and paraganglioma including a novel, recurrent and prognostic fusion gene. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4371.