Molecular Sciences & Computational Biology, Amgen, Inc., Thousand Oaks, CA
Robert D. Loberg , Rui Tang , Kelly Smith Oliner
Background: Estimates of the frequency of genomic alterations in MET and HER2 in gastric cancer vary widely, but alterations in MET are generally less common than alterations in HER2. We examined a large set of stage IV gastric cancer samples for variation in MET and HER2gene copy number. We also assessed HER2 protein expression in these samples. Methods: Formalin-fixed, paraffin-embedded (FFPE) stage IV gastric cancer tumor samples (N = 309) were collected in Russia (n = 195), China (n = 99), and other countries (n = 15). Samples were analyzed by fluorescence in situ hybridization (FISH) for MET gene amplification (Dako MET IQFISH pharmDx) and HER2 gene amplification (Dako HER2 IQFISH pharmDx) and by immunohistochemistry (IHC) for HER2 protein expression (Dako HercepTest). All assays were performed according to the manufacturer’s instructions. This is the first published use of the Dako MET IQFISH pharmDx assay. Cohen's kappa coefficient, a statistical measure that takes into account agreement that occurs by chance, was used to assess agreement between measurements. Results: We found MET gene copy number variation (≥ 5 copies) in 17 of 305 samples (6%), and MET gene amplification (MET/CEN-7 ≥ 2.0) in 12 of 305 samples (4%). The proportion of samples that were MET gene amplified was similar in the Chinese and Russian samples. We found HER2 gene copy number variation (≥ 5 copies) in 54 of 280 samples (19%), and HER2 gene amplification (HER2/CEN-17 ≥ 2.0) in 43 of 280 samples (15%). Of the 201 evaluable HER2 IHC samples, 22 (11%) were positive for HER2 protein expression. HER2 FISH and HER2 IHC results showed that HER2 gene amplification and protein expression commonly occur in the same tumors (kappa = 0.71 to 0.76). HER2 and MET FISH results showed that MET and HER2gene amplification rarely occur in the same tumors (kappa < 0.05); only one sample was amplified for both genes. Conclusions: MET gene amplification was observed in 4% of this large set of stage IV gastric cancer samples. Prevalence of HER2 gene amplification and expression was in the same range as found in previously published studies. Our results indicate that MET gene amplification and HER2 gene amplification may occur in different subpopulations of stage IV gastric cancers.
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