Gastrointestinal Stromal Tumors (GISTs), PDGFRA Mutation Analysis

CPT: 81314; 88381
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Test Details

Synonyms

  • Tyrosine Kinase Inhibitor (TKI, Imatinib) Responsiveness

Use

The platelet-derived growth factor receptor alpha (PDGFRA) gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. PDGFRA and c-KIT have approximately 35% homology. They both belong to the PDGFRA subfamily of receptor tyrosine kinases, which are involved in the regulation of cell growth, proliferation, adhesion, migration, differentiation, and apoptosis.

Limitations

Genomic DNA is purified from the specimen provided. Exons 10, 12, 14, and 18 of PDGFRA gene coding are subjected to PCR amplification and bidirectional sequencing in duplicate to identify sequence variations. This assay has a sensitivity to detect approximately 10% of cells containing the PDGFRA mutations in a background of nonmutant cells. This assay will not detect the mutation below the sensitivity of this assay.

This test was developed, and its performance characteristics determined, by LabCorp. It has not been cleared or approved by the US Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary.

Methodology

Polymerase chain reaction (PCR) and DNA sequencing

Additional Information

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, located mostly in the stomach (60%) and small intestine (35%). Approximately 80% of GISTs have a mutation in c-KIT and 5% to 10% of GISTs have a mutation in PDGFRA. PDGFRA mutations are mutually exclusive with c-KIT mutations but active similar signal transduction pathways that support GIST oncogenesis. The location of c-KIT and PDGFRA mutations in GISTs is associated with the site of origin, histological phenotype, and treatment response to tyrosine kinase inhibitors (TKI, such as imatinib and sunitinib). Patients with mutations in c-KIT exon 11 have been shown to have significantly better response rates to imatinib treatment when compared with patients who have the c-KIT exon 9 mutations or no mutation. Patients with mutations in c-KIT exon 9 may benefit from dose escalation depending on tolerance. Secondary mutations usually occur in c-KIT kinase domains in patients after imatinib treatment resulting in resistance to this drug. Other TKI inhibitors, such as sunitinib and sorafenib, could be used as a replacement drug for selected mutations. Most known mutations in the PDGFRA gene are associated with imatinib response with the exception of D842V mutation. In a subset of intestinal high-risk GISTs lacking c-KIT/PDGFRA mutations, 7% have a mutation in BRAF. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.

Specimen Requirements

Specimen

Formalin-fixed, paraffin-embedded (FFPE) tissue or five unstained slides from a paraffin block in 10-μM sections and a matching H&E reference slide

Volume

Formalin-fixed, paraffin-embedded (FFPE) block or five unstained slides from paraffin block in 10-μM sections and a matching H&E reference slide

Minimum Volume

2 mm x 2 mm tumor area with ≥50% tumor

Container

Slides or blocks

Storage Instructions

Maintain blocks and slides at room temperature.

Causes for Rejection

Tumor block containing insufficient tumor tissue or tumor fixed in a heavy metal fixative; broken or stained slides

Clinical Information

Special Instructions

Please provide a copy of the pathology report, and direct any questions regarding this test to oncology customer service at 800-345-4363.

References

Blanke CD, Demetri GD, von Mehren M, et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol. 2008 Feb 1; 26(4):620-625.18235121
Corless CL, Schroeder A, Griffith D, et al. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol. 2005 Aug 10, 23(23):5357-5364.15928335
Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009 Dec 15; 15(24):7510-7518.20008851
Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008 Nov 20; 26(33):5360-5367.18955451
NCCN Clinical Practice Guidelines in Oncology: Soft Tissue Sarcoma. Version 2.2011.
Penzel R, Aulmann S, Moock M, et al, The location of KIT and PDGFRA gene mutations in gastrointestinal stromal tumours is site and phenotype associated. J Clin Pathol. 2005 Jun; 58(6):634-63915917417

LOINC® Map

Order Code Order Code Name Order Loinc Result Code Result Code Name UofM Result LOINC
510860 PDGFRA Analysis in GISTs 510861 Mutation Analysis Result: 41103-3
510860 PDGFRA Analysis in GISTs 510862 Nucleotide Change 48004-6
510860 PDGFRA Analysis in GISTs 510863 Amino Acid Change: 48005-3
510860 PDGFRA Analysis in GISTs 510869 Block Number: N/A
510860 PDGFRA Analysis in GISTs 510864 Background: 77202-0
510860 PDGFRA Analysis in GISTs 510868 Clinical Significance N/A
510860 PDGFRA Analysis in GISTs 510865 Methodology: 49549-9
510860 PDGFRA Analysis in GISTs 510866 References: 75608-0
510860 PDGFRA Analysis in GISTs 510867 Director Review: 72486-4
510860 PDGFRA Analysis in GISTs 480903 Microdissection Performed 8100-0
510860 PDGFRA Analysis in GISTs 511978 Putaway N/A

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