Upper gastrointestinal (GI) tract malignancies, including carcinomas of the esophagus, the GI junction and the stomach, are among the most common cancers worldwide. Overall survival is poor because many patients present with locally advanced and often incurable disease. This review focuses on the pathogenesis of adenocarcinomas of the stomach. It summarises recent findings on genetic predisposition to gastric cancer, in particular in relation to germline mutations in the E-cadherin gene. It also describes the molecular basis of sporadic gastric cancer, including alterations in oncogenes, tumour suppressor genes and growth factors, and discusses how these findings might be used in the clinic for improved diagnosis and therapy.

The Raf kinases are proto-oncogenes that work at the entry point of the mitogen-activated protein kinase/extracellular-signal-regulated kinase (MAPK/ERK) pathway, a signalling module that connects cell-surface receptors and Ras proteins to nuclear transcription factors. The pathway impinges on all the functional hallmarks of cancer cells: immortalisation, growth-factor-independent proliferation, insensitivity to growth-inhibitory signals, ability to invade and metastasise, ability to attract blood vessels, and evasion of apoptosis. Indeed, the pathway is hyperactivated in 30% of all human tumours including prevalent cancers of the colon and lung. The molecular mechanisms underlying the role of Raf kinase in tumourigenesis and the opportunities for therapeutic intervention are reviewed in this article.