Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma

Lauren Fishbein, Ignaty Leshchiner, Vonn Walter, Ludmila Danilova, A. Gordon Robertson, Amy R. Johnson, Tara M. Lichtenberg, Bradley A. Murray, Hans 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 & 30 others Sylvia L. Asa, Arthur S. Tischler, Rehan Akbani, Adrian Ally, Laurence Amar, Antonio L. Amelio, Harindra Arachchi, Sylvia L. Asa, Richard J. Auchus, J. Todd Auman, Robert Baertsch, Miruna Balasundaram, Saianand Balu, Detlef K. Bartsch, Eric Baudin, Thomas Bauer, Allison Beaver, Christopher Benz, Rameen Beroukhim, Felix Beuschlein, Tom Bodenheimer, Lori Boice, Jay Bowen, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Suzie Carter, Clarissa A. Cassol, Andrew D. Cherniack, Lynda Chin

Research output: Contribution to journalArticle

  • 34 Citations

Abstract

We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

LanguageEnglish (US)
Pages181-193
Number of pages13
JournalCancer Cell
Volume31
Issue number2
DOIs
StatePublished - Feb 13 2017

Fingerprint

Paraganglioma
Pheochromocytoma
Gene Fusion
Genes
Precision Medicine
Germ-Line Mutation
Phosphotransferases

Keywords

  • CSDE1
  • expression subtypes
  • genomics
  • MAML3
  • metastasis
  • molecular profiling
  • paraganglioma
  • pheochromocytoma
  • sequencing
  • TCGA

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Fishbein, L., Leshchiner, I., Walter, V., Danilova, L., Robertson, A. G., Johnson, A. R., ... Chin, L. (2017). Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell, 31(2), 181-193. DOI: 10.1016/j.ccell.2017.01.001

Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. / Fishbein, Lauren; Leshchiner, Ignaty; Walter, Vonn; Danilova, Ludmila; Robertson, A. Gordon; Johnson, Amy R.; Lichtenberg, Tara M.; Murray, Bradley A.; Ghayee, Hans 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.; Akbani, Rehan; Ally, Adrian; Amar, Laurence; Amelio, Antonio L.; Arachchi, Harindra; Asa, Sylvia L.; Auchus, Richard J.; Auman, J. Todd; Baertsch, Robert; Balasundaram, Miruna; Balu, Saianand; Bartsch, Detlef K.; Baudin, Eric; Bauer, Thomas; Beaver, Allison; Benz, Christopher; Beroukhim, Rameen; Beuschlein, Felix; Bodenheimer, Tom; Boice, Lori; Bowen, Jay; Bowlby, Reanne; Brooks, Denise; Carlsen, Rebecca; Carter, Suzie; Cassol, Clarissa A.; Cherniack, Andrew D.; Chin, Lynda.

In: Cancer Cell, Vol. 31, No. 2, 13.02.2017, p. 181-193.

Research output: Contribution to journalArticle

Fishbein, L, Leshchiner, I, Walter, V, Danilova, L, Robertson, AG, Johnson, AR, Lichtenberg, TM, Murray, BA, Ghayee, HK, Else, T, Ling, S, Jefferys, SR, de Cubas, AA, Wenz, B, Korpershoek, E, Amelio, AL, Makowski, L, Rathmell, WK, Gimenez-Roqueplo, AP, Giordano, TJ, Asa, SL, Tischler, AS, Akbani, R, Ally, A, Amar, L, Amelio, AL, Arachchi, H, Asa, SL, Auchus, RJ, Auman, JT, Baertsch, R, Balasundaram, M, Balu, S, Bartsch, DK, Baudin, E, Bauer, T, Beaver, A, Benz, C, Beroukhim, R, Beuschlein, F, Bodenheimer, T, Boice, L, Bowen, J, Bowlby, R, Brooks, D, Carlsen, R, Carter, S, Cassol, CA, Cherniack, AD & Chin, L 2017, 'Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma' Cancer Cell, vol 31, no. 2, pp. 181-193. DOI: 10.1016/j.ccell.2017.01.001
Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR et al. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell. 2017 Feb 13;31(2):181-193. Available from, DOI: 10.1016/j.ccell.2017.01.001
Fishbein, Lauren ; Leshchiner, Ignaty ; Walter, Vonn ; Danilova, Ludmila ; Robertson, A. Gordon ; Johnson, Amy R. ; Lichtenberg, Tara M. ; Murray, Bradley A. ; Ghayee, Hans 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. ; Akbani, Rehan ; Ally, Adrian ; Amar, Laurence ; Amelio, Antonio L. ; Arachchi, Harindra ; Asa, Sylvia L. ; Auchus, Richard J. ; Auman, J. Todd ; Baertsch, Robert ; Balasundaram, Miruna ; Balu, Saianand ; Bartsch, Detlef K. ; Baudin, Eric ; Bauer, Thomas ; Beaver, Allison ; Benz, Christopher ; Beroukhim, Rameen ; Beuschlein, Felix ; Bodenheimer, Tom ; Boice, Lori ; Bowen, Jay ; Bowlby, Reanne ; Brooks, Denise ; Carlsen, Rebecca ; Carter, Suzie ; Cassol, Clarissa A. ; Cherniack, Andrew D. ; Chin, Lynda. / Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. In: Cancer Cell. 2017 ; Vol. 31, No. 2. pp. 181-193
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abstract = "We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.",
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