Universität zu Köln

Kuenstlinger, Helen, Binot, Elke, Merkelbach-Bruse, Sabine, Huss, Sebastian, Wardelmann, Eva, Buettner, Reinhard and Schildhaus, Hans-Ulrich (2014). High-resolution melting analysis is a sensitive diagnostic tool to detect imatinib-resistant and imatinib-sensitive PDGFRA exon 18 mutations in gastrointestinal stromal tumors. Hum. Pathol., 45 (3). S. 573 - 583. PHILADELPHIA: W B SAUNDERS CO-ELSEVIER INC. ISSN 1532-8392

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Abstract

The mutational status of KIT and PDGFRA is highly relevant for prognosis and therapy prediction in gastrointestinal stromal tumors (GIST). PDGFRA exon 18 mutations have direct therapeutic implications since it is crucial to distinguish mutations associated with sensitivity to tyrosine kinase inhibitors from those causing primary resistance, eg, the most common exon 18 mutation p.D842V. In response to a growing demand for reliable, faster and more sensitive methods we established and validated a high-resolution melting (BRM) assay for PDGFRA exon 18. A total of 159 GIST samples were comparatively analyzed by FIRM and direct Sanger sequencing. We demonstrate that BRM provides highly reliable mutational results with higher sensitivity and shorter time to diagnosis compared to Sanger sequencing. We determined the sensitivity threshold of FIRM at 6% of mutated alleles. PDGFRA exon 18 wild-type status and the most common p.D842V resistance mutation (together representing >90% of the cases) can be detected specifically by FIRM. Other rare mutations can be pre-screened by FIRM and afterwards determined precisely by DNA sequencing. In this way we detected four novel mutations in PDGFRA exon 18, two of which were associated with an aggressive clinical course. Including these new mutations, we provide a comprehensive overview of all 60 currently known subtypes of PDGFRA exon 18 mutations in GIST. Seven of them (accounting for about 75% of all exon 18-mutated GISTs) are reported to be resistant to imatinib. However, there are at least 10 other mutations which are regarded as sensitive to tyrosine kinase inhibitors. (C) 2014 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuenstlinger, Helen UNSPECIFIED UNSPECIFIED UNSPECIFIED Binot, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Huss, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wardelmann, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Schildhaus, Hans-Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-444948
DOI:	10.1016/j.humpath.2013.10.025
Journal or Publication Title:	Hum. Pathol.
Volume:	45
Number:	3
Page Range:	S. 573 - 583
Date:	2014
Publisher:	W B SAUNDERS CO-ELSEVIER INC
Place of Publication:	PHILADELPHIA
ISSN:	1532-8392
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GROWTH-FACTOR-RECEPTOR; ACTIVATING MUTATIONS; KIT MUTATIONS; ALPHA GENE; IN-VITRO; C-KIT; EXPRESSION; GISTS; MANAGEMENT; SPECTRUM Multiple languages Pathology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44494