MET-amplified gastric cancers exhibit co-amplifications of BRAF, CDK6, and EGFR.

Authors

Silke Lüschen, Ulrike Ebert, Hans-Michael Behrens, Sandra Krüger, Dita Ulase, Anu Amallraja, Steffen M Heckl, Thomas Becker, Philip Rosenstiel, Tobias Meißner, Christoph Röcken

Published in

The journal of pathology. Clinical research. Volume 12. Issue 4. Pages e70104.

Abstract

MET-positive gastric cancer (GC) has a poor prognosis. In addition, targeting MET with monoclonal antibodies or tyrosine kinase inhibitors had limited success. We searched for additional genetic alterations that might explain the poor outcome of MET-positive GC and lack of response to MET-targeted therapies. Multiregional whole-exome sequencing was performed on primary tumor and lymph node metastasis samples from two MET-amplified discovery cases. Immunohistochemistry, in situ hybridization, and digital droplet polymerase chain reaction were performed in a validation cohort of 24 MET-amplified GCs. Whole-exome sequencing found 191 and 166 non-synonymous mutations, respectively. Only eight genes showed non-synonymous mutations in both cases, including TP53. Copy number variations (CNVs) were found in 18 and 14 autosomes, respectively, most commonly affecting chromosome 7. Since BRAF, CDK6, and EGFR are also localized on chromosome 7, validation studies were performed by fluorescence or chromogenic in situ hybridization, and co-amplification was found in 54% of the cases, including two discovery and 24 validation cases. Different combinations were found, for example, CDK6 + MET, EGFR + MET, CDK6 + EGFR + MET, BRAF + CDK6 + EGFR + MET, or BRAF + EGFR + MET. A database search using cBioPortal confirmed our findings. However, marked intra- and intertumoral heterogeneity was observed, and CNVs were highly variable and spatially separated. MET amplification in GC is accompanied by amplification of other oncogenes located on chromosome 7, that is, BRAF, CDK6, and EGFR, in a highly heterogeneous manner leading to substantial intra- and intertumoral heterogeneity. This may cause diagnostic and therapeutic challenges, provoke subclonal evolution, and lead to poor prognosis of MET-amplified GC and the failure of targeted therapies.

PMID:
42417171
Bibliographic data and abstract were imported from PubMed on 08 Jul 2026.

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