Universität zu Köln

Castiglione, Roberta ORCID: 0000-0002-9828-4405, Alidousty, Christina, Holz, Barbara, Wagener, Svenja, Baar, Till ORCID: 0000-0002-6744-1463, Heydt, Carina, Binot, Elke, Zupp, Susann, Kron, Anna, Wolf, Juergen, Merkelbach-Bruse, Sabine, Reinhardt, Hans Christian, Buettner, Reinhard and Schultheis, Anne Maria (2019). Comparison of the genomic background of MET-altered carcinomas of the lung: biological differences and analogies. Mod. Pathol., 32 (5). S. 627 - 639. NEW YORK: NATURE PUBLISHING GROUP. ISSN 1530-0285

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Abstract

Although non-small-cell lung cancer is a leading cause of cancer-related deaths, the molecular characterization and classification of its genetic alterations has drastically changed treatment options and overall survival within the last few decades. In particular, tyrosine kinase inhibitors targeting specific molecular alterations, among other MET, have greatly improved the prognosis of non-small-cell lung cancer patients. Here, we compare the genomic background of a subset of non-small-cell lung cancer cases harboring either a MET high-level amplification (n = 24) or a MET exon 14 skipping mutation (n = 26), using next-generatison sequencing, fluorescence in situ hybridization, immunohistochemistry, and Nanostring nCounter (R) technology. We demonstrate that the MET-amplified cohort shows a higher genetic instability, compared with the mutant cohort (p < 0.001). Furthermore, MET mutations occur at high allele frequency and in the presence of co-occurring TP53 mutations (n = 7), as well as MDM2 (n = 7), CDK4 (n = 6), and HMGA2 (n = 5) co-amplifications. No other potential driver mutation has been detected. Conversely, in the MET-amplified group, we identify co-occurring pathogenic NRAS and KRAS mutations (n = 5) and a significantly higher number of TP53 mutations, compared with the MET-mutant cohort (p = 0.048). Of note, MET amplifications occur more frequently as subclonal events. Interestingly, despite the significantly (p = 0.00103) older age at diagnosis of stage IIIb/IV of MET-mutant patients (median 77 years), compared with MET high-level amplified patients (median 69 years), MET-mutant patients with advanced-stage tumors showed a significantly better prognosis at 12 months (p = 0.04). In conclusion, the two groups of MET genetic alterations differ, both clinically and genetically: our data strongly suggest that MET exon 14 skipping mutations represent an early driver mutation. In opposition, MET amplifications occur usually in the background of other strong genetic events and therefore MET amplifications should be interpreted in the context of each tumor's genetic background, rather than as an isolated driver event, especially when considering MET-specific treatment options.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Castiglione, Roberta UNSPECIFIED orcid.org/0000-0002-9828-4405 UNSPECIFIED Alidousty, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Holz, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Wagener, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Baar, Till UNSPECIFIED orcid.org/0000-0002-6744-1463 115337162 Heydt, Carina UNSPECIFIED UNSPECIFIED UNSPECIFIED Binot, Elke UNSPECIFIED UNSPECIFIED UNSPECIFIED Zupp, Susann UNSPECIFIED UNSPECIFIED UNSPECIFIED Kron, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Schultheis, Anne Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-149957
DOI:	10.1038/s41379-018-0182-8
Journal or Publication Title:	Mod. Pathol.
Volume:	32
Number:	5
Page Range:	S. 627 - 639
Date:	2019
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	NEW YORK
ISSN:	1530-0285
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SQUAMOUS-CELL; C-MET; INTRATUMOR HETEROGENEITY; DISTINCT PATTERNS; DRIVER MUTATIONS; CANCER; AMPLIFICATION; RESISTANCE; ADENOCARCINOMAS; EXPRESSION Multiple languages Pathology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14995