Germ-Line Mutations, Pancreatic Inflammation, and Pancreatic Cancer

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The fundamental problem underlying pancreatic cancer is altered genetics. Rare germ-line mutations lead to familial cancer syndromes that may include pancreatic cancer. But why do some people develop pancreatic cancer while others develop cancer in other organs, or not at all? We discuss the possibility that other common germ-line mutations diminish the ability of pancreatic cells to protect themselves from environmental or metabolic stressors, resulting in reactive molecules that lead to cell injury and DNA damage—with a series of lucky hits knocking out key tumor-suppressor genes and activating oncogenes in at least one cell with clonal growth potential. Inflammation likely accelerates this process, whether or not it is clinically evident. We also note the significant effects of smoking, alcohol, antioxidants, and diet on risk, and that together they confer a major portion of attributable risk that may be linked to the injury-inflammation-cancer pathway. Because we cannot change our genes, lifestyle choices are currently the best way to reduce pancreatic cancer risk until more effective preventative strategies are developed.

Section snippets

Familial Pancreatic Cancers

Table 1, Table 2 display the major familial cancer syndromes linked to pancreatic cancer. With the exception of hereditary pancreatitis, each of these syndromes increases the risk of cancer in multiple organs, not just in the pancreas.2 For example, the risk of pancreatic cancer is increased as much as 132-fold in Peutz–Jeghers syndrome, a cancer syndrome caused by mutations in the SKD11/LKB1 genes; individuals with Peutz–Jeghers syndrome also have an increased risk of other types of

Acquired Genetic Mutations in Pancreatic Cancer

A very important study was published recently by Jones et al11 that identified core signaling pathways that were altered by genetic mutations or chromosomal loss in human pancreatic cancer. A comprehensive genetic analysis was performed on 24 cancers with sequencing of more than 20,000 protein-coding genes, and high-density single nucleotide polymorphism analysis to analyze loss of heterozygosity, reflecting the loss of major pieces of individual chromosomes. The report by Jones et al11

Organ Targeting 1: The Role of Inflammation

One of the major complications of inflammation is the development of cancer within the inflamed tissue. The inflammation can be linked to chronic infections, continued exposure to injury or toxins, or it can be autoimmune in origin. The etiology of the inflammation does not seem to matter for cancer development. This paradigm holds true in multiple digestive system disease conditions, including the development of esophageal cancer in patients with gastroesophageal reflux and Barrett's

Organ Targeting 2: Gene-Environment Injury Without Chronic Pancreatitis

Chronic pancreatitis is a risk factor for pancreatic cancer, but most cases of pancreatic cancer develop in patients without clinical evidence of chronic pancreatitis. However, clinical evidence of chronic pancreatitis should be considered a very insensitive biomarker of pancreatic injury and inflammation. In fact, animal experiments have taught us that it is very difficult to induce chronic pancreatitis after pancreatic injury unless multiple factors, including inducing significant injury and

Smoking and Pancreatic Cancer

The single environmental factor shown to be of great risk for pancreatic cancer is cigarette smoking, which is estimated to account for approximately 25% to 30% of all pancreatic tumors.40, 41 A recent interview-based study of 247 pancreatic cancer case probands (and their 1816 first-degree relatives) and 420 population-based controls (and their 3157 first-degree relatives) determined that a positive family history of pancreatic cancer or ever-smoking cigarettes more than doubled the risk of

Factors Protecting the Pancreas From Pancreatic Cancer

A healthy lifestyle and good diet are currently the best way to reduce the risk of pancreatic cancer (Table 3). The importance of cyclic, pancreas-targeted injury in pancreatic carcinogenesis is strengthened by epidemiologic studies and animal studies that show a reduction of risk with consumption of antioxidant-rich foods that help neutralize these factors,46, 47, 48, 49 especially among predisposed individuals, such as smokers.50 Antioxidants are molecules that, by definition, neutralize

Summary of Pancreatic Cancer Inflammation and Prevention

Chronic inflammation promotes cancer by a variety of mechanisms, including increased cell cycling and the generation of reactive nitrogenous and oxygen species. In addition, inflammation orchestrates the tumor microenvironment and modulates the propagation, survival, and migration of tumor cells. However, there is a complementary function of the immune system. Many cellular components of the immune system contribute to cancer immunology and may suppress cancer either by immunosurveillance or by

Acknowledgments

Drs Whitcomb and Greer shared equally in the organization, focus, contents, and writing of the manuscript.

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    Conflicts of interest The authors disclose no conflicts.

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