Abstract ED02-03: Gene, environment, and risk factor interaction in pancreatic cancer
Authors: Risch Harvey A. 
Published: January 2011

Abstract
Cancer of the pancreas is the fourth most frequent cause of cancer death in the United States. It has among the worst survival of all types of cancer: Most patients die within one year of diagnosis. Over more than four decades of work, research studies in both humans and animals have identified a number of genetic and environmental risk factors for this disease, yet a clear picture of the disease etiology has remained obscure.
In animal studies, pancreatic cancer is established to be caused by exposure to N-nitrosamine compounds. Humans are exposed to these chemicals through tobacco and dietary sources. Increased risks associated with smoking and with consumption of smoked or processed meats have been observed in many studies of humans but the magnitudes of excess risk are fairly small and do not account for a large share of the disease. In humans, colonization by the stomach bacterium Helicobacter pylori has also been seen to be associated with increased risk of pancreatic cancer. Studies of this organism have not been performed in animals, but laboratory evidence concerning the gastric pathophysiology of the bacterium supports a role in pancreatic cancer. Finally, ABO blood groups A, B, and AB (i.e., non-O) have been known for more than 40 years to be associated with risk of pancreatic cancer, and a recent genome-wide association study identified this gene as containing the most significant risk association across the genome. The goal of this talk is to see how N-nitrosamines, H. pylori colonization and ABO blood group combine together to determine risk of pancreatic cancer, and what if any interactions of these exposures are relevant in explaining the causation of the disease.
Animal models most relevant for pancreatic cancer involve the application of N-nitroso compounds to Syrian golden hamsters. In this long-studied model, pancreatic ductal adenocarcinomas are typically produced from subcutaneous injections of N-nitrosamines such as BOP, HPOP, NDMA, NNK, etc. These carcinogens reach the pancreas via the bloodstream and not through reflux of duodenal contents or bile. The carcinogenic effect of continuous-exposure regimens of these N-nitrosamines appears to be due more to stimulation of S-phase DNA synthesis in the presence of adducts, particularly in the pancreatic ductal epithelium, than to induction of the DNA adducts per se. HPOP administration triples pancreatic ductular cell DNA synthesis, while having only slight effects on acinar and other cells which are resistant to carcinogenesis by HPOP in this model. In the human environment, N-nitrosamines are ubiquitous but occur at exceedingly low levels. Higher levels of exposure are achieved through tobacco and dietary sources. However, levels of N-nitrosamines reaching pancreatic ductal epithelial cells from tobacco or dietary exposures are orders of magnitude lower than concentrations used in carcinogenesis experiments, though these common types of human exposures are usually present for much longer periods of time. More than two dozen case-control and cohort studies show that cigarette smoking is related to increased risk of pancreatic cancer, and this approximately twofold increased risk is likely conveyed by the NNK or other N-nitrosamines known to be present in mainstream and sidestream tobacco smoke. The other main route of human exposure to N-nitrosamines is ingestion from dietary sources. N-nitrosamines (primarily NDMA) form in protein-containing foods dried at high temperatures (cooked bacon, dried meats) or preserved with nitrite or salt, or form endogenously in the stomach from nitrite-preserved meats. A summary analysis of the 19 studies to-date examining intakes of smoked/processed or nitrite foods shows that regular intake of such foods is associated with a significant 30% excess risk of pancreatic cancer.
Helicobacter pylori is carried by about 1/4 of Americans and in most cases the colonization is asymptomatic. However, H. pylori flourishes on the surface of non-acid secreting gut epithelium, particularly the gastric antrum, colonizes the gastric corpus when acid production there is inadequate or suppressed, and is lost from the corpus with progressive atrophy or other pre-neoplastic gastric changes. Colonization of the antrum by H. pylori causes reduction in the number and function of antral D cells, reduction in D-cell somatostatin mRNA synthesis per cell, and suppression of somatostatin. This leads to paracrine disinhibition of antral G cell function and hyperacidity. Because a second function of somatostatin is to inhibit secretion of secretin by S cells of the duodenum and proximal jejunum, in H. pylori carriers, a consequence of the hyperchlorhydria and suppressed somatostatin is a general increase in secretin and pancreatic ductal fluid and bicarbonate output. Secretin has a trophic effect on murine pancreatic growth and DNA synthesis, and in the hamster-BOP nitrosamine model, dramatically accelerates the development and frequency of pancreatic ductular adenocarcinomas caused by BOP. Thus, individuals with asymptomatic H. pylori colonization, who have increased basal secretin activity, under dietary or other exposure to N-nitrosamines, would be at increased risk of pancreatic cancer. The seven studies to-date indeed show that H. pylori colonization is associated with significantly increased risk, about 60% higher overall. Furthermore, the excess risk may be concentrated among carriers of the less-virulent CagA-negative strains of the organism. CagA-positive H. pylori is associated with corpus atrophic gastritis, hypochlorhydria and reduction of secretin stimulation, and recent work has shown increased pancreatic cancer risk only among carriers of CagA-negative strains.
Where does ABO blood group fit into the preceding etiologic mechanisms? Both old and recent studies show that non-O ABO blood group is associated with risk of pancreatic cancer. ABO blood group antigens are found on the surface of red blood cells and also on the surface of gastric mucosal epithelium. The ABO antigens which determine blood group bind at the end of carbohydrate oligosaccharide chains on the cell surface. H. pylori appears to bind to the gastric epithelium on the terminal Lewis(b) antigen sugar ring on these chains immediately adjacent to where the A and B antigens bind. The A and B antigens likely physically interact with how the H. pylori binding occurs. Individuals of O blood group do not have A or B antigens next to the Lewis(b) antigen where the H. pylori binds. In our studies, we have seen that CagA-negative H. pylori colonization is associated with almost 3-fold increased risk of pancreatic cancer among non-O individuals, but little excess risk among group O individuals. This interaction between ABO blood group, fact of H. pylori colonization and organism strain character arises because of the physiologic mechanisms underlying how these risk factors likely operate.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED02-03.