Oncogenic mutations in gastric cancer with microsatellite instability

Giovanni Corso, Sérgia Velho, Joana Paredes, Corrado Pedrazzani, Diana Martins, Fernanda Milanezi, Valeria Pascale, Carla Vindigni, Hugo Pinheiro, Marina Leite, Daniele Marrelli, Sónia Sousa, Fátima Carneiro, Carla Oliveira, Franco Roviello, Raquel Seruca

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)443-451
Number of pages9
JournalEuropean Journal of Cancer
Volume47
Issue number3
DOIs
Publication statusPublished - Feb 2011

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Keywords

  • BRAF
  • EGFR
  • Gastric cancer
  • KRAS
  • MAPK
  • MLK3
  • MSI
  • Oncogenic mutations
  • PI3K

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Corso, G., Velho, S., Paredes, J., Pedrazzani, C., Martins, D., Milanezi, F., Pascale, V., Vindigni, C., Pinheiro, H., Leite, M., Marrelli, D., Sousa, S., Carneiro, F., Oliveira, C., Roviello, F., & Seruca, R. (2011). Oncogenic mutations in gastric cancer with microsatellite instability. European Journal of Cancer, 47(3), 443-451. https://doi.org/10.1016/j.ejca.2010.09.008