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Semi-comprehensive analysis of gene amplification in gastric cancers using multiplex ligation-dependent probe
Akishi Ooi1, Takeru Oyama2, Ritsuko Nakamura2
11] Department of Molecular and Cellular Pathology, Graduate School of Medical Science, Kanazawa University, Ishikawa, Japan [2] Pathology Section, University Hospital, Kanazawa University, Ishikawa, Japan.
Abstract:
The prognosis of patients with gastric carcinomas at an advanced stage still remains dismal, and therefore novel therapeutic modalities are urgently needed. Since the successful targeting of amplified ERBB2 with a humanized monoclonal antibody, the amplified genes of other receptor tyrosine kinases such as EGFR, FGFR2, and MET, as well as those of other cell regulator genes, are being considered as candidate targets of molecular therapy. The aim of the present study was to determine the amplification status of 26 genes, which are frequently amplified in solid cancers, in advanced gastric cancers. A total of 93 formalin-fixed and paraffin-embedded advanced gastric cancer tissues were examined by multiple ligation-dependent probe amplification, and 32 cases with 'gain' or 'amplified' status of 16 genes were further examined for the respective gene amplification by fluorescence in situ hybridization (FISH) and for the respective protein overexpression by immunohistochemistry. The frequencies of gene amplifications in advanced gastric cancers were as follows: ERBB2 (13 cases, 14%), FGFR2 (7 cases, 8%), MYC (7 cases, 8%), TOP2A (7 cases, 8%), MET (4 cases, 4%), MDM2 (4 cases, 4%), CCND1 (3 cases, 3%), FGF10 (2 cases, 3%), and EGFR (1 case, 1%). Amplification of the receptor tyrosine kinases genes occurred in a mutually exclusive manner except for one tumor in which ERBB2 and FGFR2 were both amplified but in different cancer cells. Co-amplification of ERBB2 and MYC, and EGFR and CCND1, in single nuclei but on different amplicons, was confirmed in one case each. Attempts at correlating the FISH status with the immunohistochemical staining pattern showed variable results from complete concordance to no correlation. In conclusion, combination of multiple ligation-dependent probe amplification and FISH analysis is a feasible approach for obtaining the semi-comprehensive genetic information that is necessary for personalized molecular targeted therapy.
Insights
Novel molecular therapies are needed for advanced gastric cancer. This study identified frequent gene amplifications, including ERBB2 and FGFR2, offering potential targets for personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Advanced gastric cancer has a poor prognosis, necessitating new therapeutic approaches.
- Targeting amplified receptor tyrosine kinases (RTKs) is a promising strategy for molecular therapy.
- Previous successes with ERBB2-targeted therapy highlight the potential of gene amplification as a therapeutic target.
Purpose of the Study:
- To determine the amplification status of 26 frequently amplified genes in advanced gastric cancers.
- To identify potential molecular targets for personalized therapy in gastric cancer patients.
- To investigate the co-amplification patterns and correlations with protein expression.
Main Methods:
- Utilized multiple ligation-dependent probe amplification (MLPA) on 93 advanced gastric cancer tissues.
- Confirmed gene amplification using fluorescence in situ hybridization (FISH) for 16 selected genes.
- Assessed protein overexpression via immunohistochemistry (IHC) to correlate with gene amplification status.
Main Results:
- Identified frequent gene amplifications: ERBB2 (14%), FGFR2 (8%), MYC (8%), TOP2A (8%), MET (4%), MDM2 (4%), CCND1 (3%), FGF10 (3%), and EGFR (1%).
- Observed mutually exclusive amplification of RTK genes, with exceptions noted for ERBB2/FGFR2 and ERBB2/MYC co-amplification.
- Found variable correlation between FISH results and IHC protein expression levels.
Conclusions:
- MLPA combined with FISH provides comprehensive genetic information for personalized molecular targeted therapy in gastric cancer.
- Identifying specific gene amplifications like ERBB2 and FGFR2 is crucial for guiding treatment decisions.
- Further research is needed to fully elucidate the relationship between gene amplification and protein expression for optimal therapeutic targeting.
