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

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

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

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

Permalink

Publisher:: AMER ASSOC CANCER RESEARCH
Publication Type:: Journal Article
Citation:: Cancer Discov, 2014, 4, (2), pp. 216-231
Issue Date:: 2014-02

Closed Access

	Filename	Description	Size
	Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fus.pdf	Published version	1.45 kB	Adobe PDF	View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Shern, JF
dc.contributor.author	Chen, L
dc.contributor.author	Chmielecki, J
dc.contributor.author	Wei, JS
dc.contributor.author	Patidar, R
dc.contributor.author	Rosenberg, M
dc.contributor.author	Ambrogio, L
dc.contributor.author	Auclair, D
dc.contributor.author	Wang, J
dc.contributor.author	Song, YK
dc.contributor.author	Tolman, C
dc.contributor.author	Hurd, L
dc.contributor.author	Liao, H
dc.contributor.author	Zhang, S
dc.contributor.author	Bogen, D
dc.contributor.author	Brohl, AS
dc.contributor.author	Sindiri, S
dc.contributor.author	Catchpoole, D https://orcid.org/0000-0001-5836-1413
dc.contributor.author	Badgett, T
dc.contributor.author	Getz, G
dc.contributor.author	Mora, J
dc.contributor.author	Anderson, JR
dc.contributor.author	Skapek, SX
dc.contributor.author	Barr, FG
dc.contributor.author	Meyerson, M
dc.contributor.author	Hawkins, DS
dc.contributor.author	Khan, J
dc.date.accessioned	2024-11-04T01:11:52Z
dc.date.available	2024-11-04T01:11:52Z
dc.date.issued	2014-02
dc.identifier.citation	Cancer Discov, 2014, 4, (2), pp. 216-231
dc.identifier.issn	2159-8274
dc.identifier.issn	2159-8290
dc.identifier.uri	http://hdl.handle.net/10453/181685
dc.description.abstract	UNLABELLED: 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. SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	AMER ASSOC CANCER RESEARCH
dc.relation.ispartof	Cancer Discov
dc.relation.isbasedon	10.1158/2159-8290.CD-13-0639
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Chromosome Aberrations
dc.subject.mesh	Class I Phosphatidylinositol 3-Kinases
dc.subject.mesh	Cluster Analysis
dc.subject.mesh	DNA Copy Number Variations
dc.subject.mesh	Exome
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Gene Rearrangement
dc.subject.mesh	Gene Regulatory Networks
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	Genomics
dc.subject.mesh	Genotype
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mutation
dc.subject.mesh	Oncogene Proteins, Fusion
dc.subject.mesh	Paired Box Transcription Factors
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Proto-Oncogene Proteins p21(ras)
dc.subject.mesh	Receptors, Fibroblast Growth Factor
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Chromosome Aberrations
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Receptors, Fibroblast Growth Factor
dc.subject.mesh	Oncogene Proteins, Fusion
dc.subject.mesh	Cluster Analysis
dc.subject.mesh	Genomics
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Gene Rearrangement
dc.subject.mesh	Genotype
dc.subject.mesh	Mutation
dc.subject.mesh	Proto-Oncogene Proteins p21(ras)
dc.subject.mesh	Paired Box Transcription Factors
dc.subject.mesh	Gene Regulatory Networks
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	DNA Copy Number Variations
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Class I Phosphatidylinositol 3-Kinases
dc.subject.mesh	Exome
dc.subject.mesh	Animals
dc.subject.mesh	Cell Cycle Proteins
dc.subject.mesh	Chromosome Aberrations
dc.subject.mesh	Class I Phosphatidylinositol 3-Kinases
dc.subject.mesh	Cluster Analysis
dc.subject.mesh	DNA Copy Number Variations
dc.subject.mesh	Exome
dc.subject.mesh	Gene Expression Regulation, Neoplastic
dc.subject.mesh	Gene Rearrangement
dc.subject.mesh	Gene Regulatory Networks
dc.subject.mesh	Genome-Wide Association Study
dc.subject.mesh	Genomics
dc.subject.mesh	Genotype
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Mutation
dc.subject.mesh	Oncogene Proteins, Fusion
dc.subject.mesh	Paired Box Transcription Factors
dc.subject.mesh	Phosphatidylinositol 3-Kinases
dc.subject.mesh	Proto-Oncogene Proteins p21(ras)
dc.subject.mesh	Receptors, Fibroblast Growth Factor
dc.subject.mesh	Rhabdomyosarcoma
dc.subject.mesh	Signal Transduction
dc.title	Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.
dc.type	Journal Article
utslib.citation.volume	4
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Computer Science
pubs.organisational-group	University of Technology Sydney/UTS Groups
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)
pubs.organisational-group	University of Technology Sydney/UTS Groups/Digital, Virtual and AI in Health Collaborative (DVAIHC)
pubs.organisational-group	University of Technology Sydney/UTS Groups/INSIGHT: Institute for Innovative Solutions for Well-being and Health
pubs.organisational-group	University of Technology Sydney/UTS Groups/Australian Artificial Intelligence Institute (AAII)/Australian Artificial Intelligence Institute (AAII) Associate Member
pubs.organisational-group	University of Technology Sydney/UTS Groups/The Trustworthy Digital Society
utslib.copyright.status	closed_access	*
dc.date.updated	2024-11-04T01:11:50Z
pubs.issue	2
pubs.publication-status	Published
pubs.volume	4
utslib.citation.issue	2

Abstract:

UNLABELLED: 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. SIGNIFICANCE: This is the most comprehensive genomic analysis of rhabdomyosarcoma to date. Despite a relatively low mutation rate, multiple genes were recurrently altered, including NRAS, KRAS, HRAS, FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR. In addition, a majority of rhabdomyosarcoma tumors alter the receptor tyrosine kinase/RAS/PIK3CA axis, providing an opportunity for genomics-guided intervention.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/181685