Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors

Jack F. Shern; Li Chen; Juliann Chmielecki; Jun S. Wei; Rajesh Patidar; Mara Rosenberg; Lauren Ambrogio; Daniel Auclair; Jianjun Wang; Young K. Song; Catherine Tolman; Laura Hurd; Hongling Liao; Shile Zhang; Dominik Bogen; Andrew S. Brohl; Sivasish Sindiri; Daniel Catchpoole; Thomas Badgett; Gad Getz; Jaume Mora; James R. Anderson; Stephen X. Skapek; Frederic G. Barr; Matthew Meyerson; Douglas S. Hawkins; Javed Khan

doi:10.1158/2159-8290.CD-13-0639

Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors

Jack F. Shern, Li Chen, Juliann Chmielecki, Jun S. Wei, Rajesh Patidar, Mara Rosenberg, Lauren Ambrogio, Daniel Auclair, Jianjun Wang, Young K. Song, Catherine Tolman, Laura Hurd, Hongling Liao, Shile Zhang, Dominik Bogen, Andrew S. Brohl, Sivasish Sindiri, Daniel Catchpoole, Thomas Badgett, Gad GetzJaume Mora, James R. Anderson, Stephen X. Skapek, Frederic G. Barr, Matthew Meyerson, Douglas S. Hawkins, Javed Khan

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534 Scopus citations

Abstract

Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/ normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/ RAS / PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.

Original language	English (US)
Pages (from-to)	216-231
Number of pages	16
Journal	Cancer discovery
Volume	4
Issue number	2
DOIs	https://doi.org/10.1158/2159-8290.CD-13-0639
State	Published - Feb 2014

ASJC Scopus subject areas

Oncology

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Shern, J. F., Chen, L., Chmielecki, J., Wei, J. S., Patidar, R., Rosenberg, M., Ambrogio, L., Auclair, D., Wang, J., Song, Y. K., Tolman, C., Hurd, L., Liao, H., Zhang, S., Bogen, D., Brohl, A. S., Sindiri, S., Catchpoole, D., Badgett, T., ... Khan, J. (2014). Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer discovery, 4(2), 216-231. https://doi.org/10.1158/2159-8290.CD-13-0639

Shern, JF, Chen, L, Chmielecki, J, Wei, JS, Patidar, R, Rosenberg, M, Ambrogio, L, Auclair, D, Wang, J, Song, YK, Tolman, C, Hurd, L, Liao, H, Zhang, S, Bogen, D, Brohl, AS, Sindiri, S, Catchpoole, D, Badgett, T, Getz, G, Mora, J, Anderson, JR, Skapek, SX, Barr, FG, Meyerson, M, Hawkins, DS & Khan, J 2014, 'Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors', Cancer discovery, vol. 4, no. 2, pp. 216-231. https://doi.org/10.1158/2159-8290.CD-13-0639

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title = "Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors",

abstract = "Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/ normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/ RAS / PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.",

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AU - Chen, Li

AU - Chmielecki, Juliann

AU - Wei, Jun S.

AU - Patidar, Rajesh

AU - Rosenberg, Mara

AU - Ambrogio, Lauren

AU - Auclair, Daniel

AU - Wang, Jianjun

AU - Song, Young K.

AU - Tolman, Catherine

AU - Hurd, Laura

AU - Liao, Hongling

AU - Zhang, Shile

AU - Bogen, Dominik

AU - Brohl, Andrew S.

AU - Sindiri, Sivasish

AU - Catchpoole, Daniel

AU - Badgett, Thomas

AU - Getz, Gad

AU - Mora, Jaume

AU - Anderson, James R.

AU - Skapek, Stephen X.

AU - Barr, Frederic G.

AU - Meyerson, Matthew

AU - Hawkins, Douglas S.

AU - Khan, Javed

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N2 - Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/ normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/ RAS / PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.

AB - Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, whole-exome, and transcriptome sequencing to characterize the landscape of somatic alterations in 147 tumor/ normal pairs. Two genotypes are evident in rhabdomyosarcoma tumors: those characterized by the PAX3 or PAX7 fusion and those that lack these fusions but harbor mutations in key signaling pathways. The overall burden of somatic mutations in rhabdomyosarcoma is relatively low, especially in tumors that harbor a PAX3/7 gene fusion. In addition to previously reported mutations in NRAS, KRAS, HRAS, FGFR4, PIK3CA, and CTNNB1, we found novel recurrent mutations in FBXW7 and BCOR, providing potential new avenues for therapeutic intervention. Furthermore, alteration of the receptor tyrosine kinase/ RAS / PIK3CA axis affects 93% of cases, providing a framework for genomics-directed therapies that might improve outcomes for patients with rhabdomyosarcoma.

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Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors

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