What Causes Pancreatic Cancer?
There isn’t a single cause of pancreatic cancer, but rather several factors—environmental or inherited—that can result in mutations to DNA.
Genes and Pancreatic Cancer
All the cells in the body contain DNA, the molecule in the cell nucleus that carries the instructions (genes) for making living organisms. When cells grow and divide, they also copy their DNA.
Research conducted by Dr. Vogelstein at Johns Hopkins found that random, unpredictable ‘mistakes’ that occur when DNA is copied account for nearly two-thirds of cancer mutations, and that environmental factors account for another 29%. Mutations in DNA occur frequently, especially when cells divide. Cells have an exceptional ability to repair these changes in DNA. However, the DNA repair mechanisms can also fail. When they do, these mistakes in DNA can be passed along to future copies of the altered cell. More abnormal cells can then be produced and when these abnormal cells continue to grow unchecked, cancer may develop.
The DNA mutations that cause pancreatic cancer may be either inherited from a parent or acquired as we age. Not everyone who has an inherited mutation will develop pancreatic cancer. In fact, pancreatic cancer is relatively rare, striking 12 to 13 people per 100,000 each year, so even doubling a rare risk still means that the risk is very low.
Acquired mutations are ones that develop during a person’s lifetime, either as random mutations in DNA or in response to injuries from harmful environmental factors such as exposure to carcinogens in tobacco smoke or cosmic rays. Scientists believe most cancers result from complex DNA changes that involve many different genes.Not everyone who has an acquired mutation will develop pancreatic cancer.
Family History and Pancreatic Cancer
Relatives of patients with pancreatic cancer may have an increased risk of developing the disease. The risk depends on the gene inherited, however, not everyone with a family history of pancreatic cancer or inherited mutation will develop the disease.
If the gene inherited isn’t known, inherited risk can be estimated based on the number of first-degree relatives (a sibling, parent, or child) who have been diagnosed with pancreatic cancer. One first-degree relative with pancreatic cancer means a two to four-fold risk, two relatives increase the risk by six or seven-fold, and three first-degree relatives, which is highly unusual, results in a 32-fold risk. Having a family member who had pancreatic cancer younger than 50 years of age is an added risk of pancreatic cancer.
Inherited mutations in known cancer-causing genes such as BRCA2, BRCA1, PALB2, p16/CDKN2A, ATM, STK11, PRSS1, SPINK1 and in one of the DNA mismatch repair (DNA is not properly repaired) genes have been shown to increase the risk of developing pancreatic cancer. These genes are therefore called familial pancreatic cancer genes.
It is estimated 10% of pancreatic cancer is familial. Researchers around the world have set up pancreatic cancer registries to study the hereditary factors that influence pancreatic cancer.
Screening programs are currently being explored for patients with a known genetic abnormality that predisposes them to pancreatic cancer or who have a strong family history of pancreatic cancer. These screening programs may be useful for identifying early pancreatic tumors.
Hereditary Syndromes
Hereditary syndromes are inherited genetic mutations in one or more genes that may predispose the affected individuals to the development of certain cancers and may also cause the early age of onset of these cancers. The hereditary syndromes listed below have been associated with the development of pancreatic cancer.
Familial Breast Cancer Syndrome
People who have the breast cancer 2 gene (BRCA2) mutation have an increased risk of several cancers, among them pancreatic. Inherited mutations in the BRCA2 gene are particularly common in the Ashkenazi Jewish population. It has recently been suggested that cancers arising in patients with a BRCA2 mutation may be particularly sensitive to treatment with drugs called PARP inhibitors. Although the association is not as strong as it is with BRCA2, inherited mutations in the first breast cancer gene, BRCA1, may also increase the risk of pancreatic cancer.
Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome
People with FAMMM syndrome, also called p16-Leiden, have many different-sized skin moles that are asymmetrical and raised. Most cases of FAMMM syndrome are caused by inherited mutations in the p16/CDKN2A gene.
Peutz-Jeghers Syndrome (PJS)
People with this rare syndrome have mutations in the STK11/LKB1 gene. Polyps in the small intestine and dark spots on the mouth and fingers characterize the syndrome. In people with PJS, the risks of gastrointestinal tumors such as esophageal, small bowel, colorectal, and pancreatic cancer are increased.
Hereditary Pancreatitis
Hereditary pancreatitis is a rare disease in which patients develop recurrent episodes of severe recurrent pancreatitis at an early age. The main genes related to this disorder are PRSS1, SPINK1, and the cystic fibrosis gene, CFTR. About 30% to 40% of people with hereditary pancreatitis will develop pancreatic cancer by age 70, and the risk is especially high among patients with hereditary pancreatitis who also smoke cigarettes.
Hereditary Nonpolyposis Colon Cancer (HNPCC; Lynch Syndrome)
People with HNPCC have a higher-than-normal chance of developing colon, pancreatic, uterine, stomach, or ovarian cancer. People with this disorder have inherited mutations in DNA mismatch repair genes. Recently it has been shown the drug KeytrudaⓇ (pembrolizumab) may be very effective in the treatment of cancers that arise in patients with HNPCC who develop pancreatic cancer.
Partner and Localizer of BRCA2 (PALB2)
Mutations in this gene, which is related to BRCA2, also increase the risk of breast and pancreatic cancer.
ATM
Mutations in this gene may increase the risk of pancreatic cancer.
What are the Risk Factors of Pancreatic Cancer?
Risk factors are characteristics, habits or environmental exposures that have been shown to increase the odds of developing a disease. Some can be controlled, while others cannot.
Smoking
Smoking or being exposed to secondhand smoke is the leading preventable cause of pancreatic cancer. People who smoke have twice the chance of getting pancreatic cancer compared with people who do not smoke. Importantly, the risk of cancer falls after smoking cessation. Over time, smokers who quit will decrease their risk of developing pancreatic cancer, and after 10 years the risk in ex-smokers is the same as that of nonsmokers.
Obesity
Significantly overweight people are more likely to develop pancreatic cancer compared with those who are not overweight, with those patients who are obese during their teens and twenties having the highest risk.
Age
As people get older, their risk of pancreatic cancer increases. Pancreatic cancer mostly affects people 55 years of age or older.
Race
In the United States, pancreatic cancer is more common in African Americans than in Caucasians, although the reasons are not clear. Differences in dietary habits, the rates of obesity and diabetes, and the frequency of cigarette smoking exist between these groups. Genetic or other unknown factors may also explain the higher incidence in African Americans.
Medical Factors
The incidence of pancreatic cancer is higher in people who have any of the following medical conditions:
- Chronic pancreatitis (inflammation that causes irreversible damage to the pancreas)
- Long-term diabetes mellitus (high blood sugar)
- Helicobacter pylori infection or ulcers
Adult Onset Diabetes
New onset diabetes in an older person can be the first sign of pancreatic cancer. In fact, up to 80% of patients with pancreatic cancer are either prediabetic or are in a presymptomatic phase of diabetes.
Presence of Risk Factors
When an individual has one, or even more than one, of these risk factors, it does not mean that person will develop pancreatic cancer. Conversely, some people who do not have any risk factors will still get pancreatic cancer. Researchers are working to understand how lifestyle and environmental risk factors interact with an individual’s genetic makeup to influence pancreatic cancer development.