Oncogenic mutations in gastric cancer with microsatellite instability

• Published in: European journal of cancer (1990) 2011-02, Vol.47 (3), p.443-451
• Main Authors: Corso, Giovanni, Velho, Sérgia, Paredes, Joana, Pedrazzani, Corrado, Martins, Diana, Milanezi, Fernanda, Pascale, Valeria, Vindigni, Carla, Pinheiro, Hugo, Leite, Marina, Marrelli, Daniele, Sousa, Sónia, Carneiro, Fátima, Oliveira, Carla, Roviello, Franco, Seruca, Raquel
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Biomarkers, Tumor - genetics; BRAF; Class I Phosphatidylinositol 3-Kinases; EGFR; ErbB Receptors - genetics; Female; Gastric cancer; Gene Amplification; Genetic Testing; Hematology, Oncology and Palliative Medicine; Humans; Immunohistochemistry; KRAS; Male; MAP Kinase Kinase Kinases - genetics; MAPK; Medical sciences; Microsatellite Instability; Mitogen-Activated Protein Kinase Kinase Kinase 11; Mitogen-Activated Protein Kinases - genetics; MLK3; MSI; Mutation - genetics; Oncogenic mutations; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - genetics; PI3K; Polymerase Chain Reaction; Proto-Oncogene Proteins - genetics; Stomach Neoplasms - genetics; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2010.09.008

Abstract Aim Mitogen-activated protein kinase ( MAPK ) cascade and phosphatidylinositol 3-kinase ( PI3K ) survival pathways are frequently activated in the progression of gastrointestinal malignancies. In this study, we aimed to determine the frequency of gene mutations in members of these pathways – Epithelial Growth Factor Receptor ( EGFR ) , KRAS, BRAF, PIK3CA and MLK3 in a series of 63 gastric carcinomas with high levels of microsatellite instability (MSI). Methods Gene mutation analysis was performed by PCR amplification followed by direct sequencing. In selected tumour cases, EGFR expression was evaluated by immunohistochemistry. Association studies between molecular data and clinicopathologic characteristics were performed. Results Mutations in EGFR (3′-untranslated region [UTR] polyA repeat), KRAS , PIK3CA and MLK3 genes occurred in 30 (47.6%), 11 (17.5%), 9 (14.3%) and 2 (3.2%) of the MSI gastric cancer (GC) cases, respectively. No BRAF or EGFR hotspot mutations were identified. Overall, mutations in at least one of these genes were found in 55.6% (35/63) of gastric carcinomas. From those mutant cases 40.0% (14/35) of them had concomitant gene mutations, always involving EGFR polyA deletions. Interestingly, we observed significant associations between oncogenic mutations and female gender ( p = 0.046) old age of diagnosis ( p = 0.001) and intestinal subtype ( p = 0.043). Conclusion Our results show that MSI gastric carcinoma frequently shows activation of EGFR - MAPK and PI3K pathways. Within all alterations found, deletions of the A13 repeats of EGFR were common, suggesting this molecular event as an important biomarker for stratification of GC patients for treatment with EGFR inhibitors.