Genetic predisposition to gastro-oesophageal cancer

Gastro-oesophageal cancers were ranked as the second cause of death from cancer worldwide despite a steady decrease in incidence for squamous cell carcinoma (SCC) of the oesophagus and distal gastric cancers. Adenocarcinoma of the oesophagus (OAC) is the tumour whose incidence has seen the highest increase in the past 30 years. Most of these cancers are strongly associated with environmental and life style risk factors such as smoking and alcohol for SCC, gastro-oesophageal reflux for OAC and Helicobacter pylori for distal gastric cancer. It may therefore be unsurprising that SCC is associated with polymorphisms in ALDH2 and ADH1B1, enzyme involved in alcohol metabolism, and with CYP1A1, involved in xenobiotics detoxification. OAC, whose incidence in absolute terms remains low, has been much less studied and at best the associations identified with risk are weak. Diffuse type gastric cancers while relatively uncommon have a strong genetic association with mutation of the CDH1 gene and prostate specific cancer antigen (PSCA) was demonstrated in a GWAS to be associated with an increased risk of diffuse gastric cancer but not intestinal type gastric cancer. This family of cancer is more associated with polymorphisms at the IL-1beta, IL-1RN loci and MHTFR loci. Specific strains of H pylori containing the virulence factors VacA s1, VacA m1 and cag A together with polymorphism at the IL-1beta and IL-1RN loci have up to a 87-fold increase in risk for developing intestinal type gastric cancer. While progress has been made to identify genetic variants associated with upper-gastrointestinal cancers, the relative small prevalence for some subtypes underlies the need for consortia, especially in view of the large variations in the prevalence of polymorphisms between different populations.