Bacteria may signal pancreatic cancer risk

A new study finds significant associations between antibodies for multiple oral bacteria and the risk of pancreatic cancer, adding support for the emerging idea that the ostensibly distant medical conditions are related.

The study of blood samples from more than 800 European adults, published in the journal Gut, found that high antibody levels for one of the more infectious periodontal bacterium strains of Porphyromonas gingivalis were associated with a two-fold risk for pancreatic cancer. Meanwhile, study subjects with high levels of antibodies for some kinds of harmless “commensal” oral bacteria were associated with a 45-percent lower risk of pancreatic cancer.

“The relative increase in risk from smoking is not much bigger than two,” said Brown University epidemiologist Dominique Michaud, the paper’s corresponding author. “If this is a real effect size of two, then potential impact of this finding is really significant.”

Pancreatic cancer, which is difficult to detect and kills most patients within six months of diagnosis, is responsible for 40,000 deaths a year in the United States.

Several researchers, including Michaud, have found previous links between periodontal disease and pancreatic cancer. The Gut paper is the first study to test whether antibodies for oral bacteria are indicators of pancreatic cancer risk and the first study to associate the immune response to commensal bacteria with pancreatic cancer risk. The physiological mechanism linking oral bacteria and pancreatic cancer remains unknown, but the study strengthens the suggestion that there is one.

“This is not an established risk factor,” said Michaud, who is also co-lead author with Jacques Izard, of the Forsyth Institute and Harvard University. “But I feel more confident that there is something going on. It’s something we need to understand better.”

Pancreatic cancer is highly lethal and difficult to detect early. In a new study, researchers report that people who had high levels of antibodies for an infectious oral bacterium turned out to have double the risk for developing the cancer. High antibody levels for harmless oral bacteria, meanwhile, predicted a reduced pancreatic cancer risk.

Izard, a microbiologist, said the importance of bacteria in cancer is growing. “The impact of immune defense against both commensals and pathogenic bacteria undeniably plays a role,” he said. “We need to further investigate the importance of bacteria in pancreatic cancer beyond the associated risk.”

Prospective, controlled study

To conduct their research, Michaud and Izard drew on medical records and preserved blood samples collected by the Imperial College-led European Prospective Investigation into Cancer and Nutrition Study, a massive dataset of more than 500,000 adults in 10 countries. Detailed health histories and blood samples are available from more than 380,000 of the participants.

From that population, the researchers found 405 people who developed pancreatic cancer, but no other cancer, and who had blood samples available. The researchers also selected 416 demographically similar people who did not develop pancreatic cancer for comparison.

Cigarette smoking and tobacco

A study published in December 2011 estimated that around 29% of pancreatic cancers in the UK in 2010 were caused by smoking.  A British study reported that ex-smokers were 1.4 times more likely to die of pancreatic cancer compared with men who had never smoked. Current smokers of less than 25 cigarettes a day had 1.8 times the risk of death and smokers of 25 or more cigarettes a day were at 3.1 times the risk of never smokers.

Prospective studies have reported a positive trend with number of years of smoking among men but not women.  Smokers are diagnosed on average 10 years younger than non-smokers.  Some studies have reported that it takes 10-20 years after cessation for risk to return to the level of a never-smoker, but recent results from the European Prospective Investigation into Cancer and Nutrition (EPIC) showed that risk fell to the level of a never-smoker within five years of giving up. While the chemical cause is unclear, it is possible that N-nitroso compounds in tobacco are carried to the pancreas in the blood. Regular cigar and/or pipe smokers have a 50% increased risk of pancreatic cancer.

The International Agency for Research on Cancer states that smokeless tobacco smoke increases the risk of pancreatic cancer. There is evidence that risk increases with the use of snus,  and it has been estimated that one in five cases of pancreatic cancer in Swedish men are due to this factor.

According to EPIC, secondhand smoke exposure at home or at work increases the risk of pancreatic cancer by about 50%, and daily exposure in childhood doubles the risk of pancreatic cancer in later life. An American study showed that offspring of women who smoke have a 40% increased risk.However, a Candadian case-control study and the Netherlands cohort study showed no significant risk increase with secondhand smoke exposure.

The researchers blinded themselves to which samples came from cancer patients and which didn’t during their analysis of the blood, which consisted of measuring antibody concentrations for 25 pathogenic and commensal oral bacteria. In their study design and analysis they controlled for smoking, diabetes, body mass index, and other risk factors.

An important element of the study design was that date of the blood samples preceded the diagnosis of pancreatic cancer by as much as a decade, meaning that the significant difference in antibody levels were likely not a result of cancer.

What are risk factors for pancreatic cancer?

There are some factors which can increase the risk of acquiring the genetic mutations that may potentially result in pancreatic cancer. These risk factors are outlined in the table below. You will notice that coffee and alcohol are not listed. Currently there is not strong evidence to suggest that consumption of either substance will increase your risk for developing cancer of the pancreas.

  Cigarette smoking
  Cigarette smoke contains a large number of carcinogens (cancer causing chemicals). Therefore, it is not surprising that cigarette smoking is one of the biggest risk factors for developing pancreatic cancer. For example, smoking during college has been associated with a 2-3 fold increased risk of pancreatic cancer.
  The risk of developing pancreatic cancer increases with age. Over 80% of the cases develop between the ages of 60 and 80.
  Studies in the United States have shown that pancreatic cancer is more common in the African-American population than it is in the white population. Some of this increased risk may be due to socioeconomic factors and to cigarette smoking.
  Cancer of the pancreas is more common in men than in women. This may be, in part, because men are more likely to smoke than women.
  Religious Background
  Pancreatic cancer is proportionally more common in Jews than the rest of the population. This may be because of a particular inherited mutation in the breast cancer gene (BRCA2) which runs in some Jewish families.
  Chronic pancreatitis
  Long-term inflammation of the pancreas (pancreatitis) has been linked to cancer of the pancreas. The reason for this association is not clear, but it is greatest in patients with inherited chronic pancreatitis.
  Diabetes Mellitus (also known as sugar diabetes) is a disease in which the body does not produce adequate amounts of insulin. Insulin is a hormone normally made by the pancreas. Insulin helps the body convert sugars and starches into energy. Diabetes has been linked to pancreatic cancer. Diabetes appears to be both a symptom of pancreatic cancer, and long-standing adult-onset diabetes may also increase the risk of developing pancreatic cancer. Recent studies have shown that 1% of patients diagnosed with diabetes after the age of 50 years will be diagnosed with pancreatic cancer within 3 years of their diagnosis of diabetes (Link here to PubMed- Probability of pancreatic cancer following diabetes: a population-based study.Gastroenterology. 2005 Aug;129(2):504-11. PMID: 16083707 ). Although prelimminary, studies such as these suggest that new onset diabetes in a person over the age of 50 may be an early warning sign of pancreatic cancer.
  Peptic ulcer surgery
  Patients who have had a portion of their stomach removed (partial gastrectomy) appear to have an increased risk for developing pancreatic cancer.
  Diets high in meats, cholesterol fried foods and nitrosamines may increase the risk, while diets high in fruits and vegetables may reduce the risk of pancreatic cancer.

Instead, the underlying mechanisms that link Porphyromonas gingivalis to pancreatic cancer could be causal, Michaud said, although much more research is needed to understand this association.

Meanwhile, the researchers speculate, the association of high levels of antibodies for commensal bacteria and pancreatic cancer, may indicate an innate, highly active immune response that is protective against cancer.

“Genetic determinants of immune surveillance clearly play a critical role in pancreatic cancer development,” the authors wrote. “Consequently, it is plausible that elevated levels of antibodies to oral bacteria in individuals serve as a marker for a genetically stronger immune response, providing protection against carcinogenesis.”

Michaud, who studies cancer risk factors generally, continues to investigate the association between oral bacteria and pancreatic cancer in collaboration with Izard.

The National Cancer Institute was the primary funder of the study.
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