PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib

Christopher Corless, Arin Schroeder, Diana Griffith, Ajia Town, Laura McGreevey, Patina Harrell, Sharon Shiraga, Troy Bainbridge, Jason Morich, Michael Heinrich

Research output: Contribution to journalArticle

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Abstract

Purpose: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. Materials and Methods: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. Results: There were 80 tumors (7.2%) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. Conclusion: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.

Original languageEnglish (US)
Pages (from-to)5357-5364
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number23
DOIs
StatePublished - 2005
Externally publishedYes

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Platelet-Derived Growth Factor alpha Receptor
Gastrointestinal Stromal Tumors
Mutation
Exons
Protein Isoforms
Phosphotransferases
In Vitro Techniques
Imatinib Mesylate
CHO Cells
Codon
Protein-Tyrosine Kinases
Neoplasms
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

PDGFRA mutations in gastrointestinal stromal tumors : Frequency, spectrum and in vitro sensitivity to imatinib. / Corless, Christopher; Schroeder, Arin; Griffith, Diana; Town, Ajia; McGreevey, Laura; Harrell, Patina; Shiraga, Sharon; Bainbridge, Troy; Morich, Jason; Heinrich, Michael.

In: Journal of Clinical Oncology, Vol. 23, No. 23, 2005, p. 5357-5364.

Research output: Contribution to journalArticle

Corless, C, Schroeder, A, Griffith, D, Town, A, McGreevey, L, Harrell, P, Shiraga, S, Bainbridge, T, Morich, J & Heinrich, M 2005, 'PDGFRA mutations in gastrointestinal stromal tumors: Frequency, spectrum and in vitro sensitivity to imatinib', Journal of Clinical Oncology, vol. 23, no. 23, pp. 5357-5364. https://doi.org/10.1200/JCO.2005.14.068
Corless, Christopher ; Schroeder, Arin ; Griffith, Diana ; Town, Ajia ; McGreevey, Laura ; Harrell, Patina ; Shiraga, Sharon ; Bainbridge, Troy ; Morich, Jason ; Heinrich, Michael. / PDGFRA mutations in gastrointestinal stromal tumors : Frequency, spectrum and in vitro sensitivity to imatinib. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 23. pp. 5357-5364.
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abstract = "Purpose: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. Materials and Methods: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. Results: There were 80 tumors (7.2{\%}) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. Conclusion: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6{\%}) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.",
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T1 - PDGFRA mutations in gastrointestinal stromal tumors

T2 - Frequency, spectrum and in vitro sensitivity to imatinib

AU - Corless, Christopher

AU - Schroeder, Arin

AU - Griffith, Diana

AU - Town, Ajia

AU - McGreevey, Laura

AU - Harrell, Patina

AU - Shiraga, Sharon

AU - Bainbridge, Troy

AU - Morich, Jason

AU - Heinrich, Michael

PY - 2005

Y1 - 2005

N2 - Purpose: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. Materials and Methods: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. Results: There were 80 tumors (7.2%) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. Conclusion: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.

AB - Purpose: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. Materials and Methods: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. Results: There were 80 tumors (7.2%) with a PDGFRA mutation: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. Conclusion: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.

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