Pancreatic cancer is relatively uncommon, with a lifetime risk of ~1.5% for individuals in the United States. For the majority of pancreatic cancers, the cause is unknown and there is no known family history of the disease. In these circumstances, a cancer is typically termed “sporadic.” General population risk factors that increase the risk for developing pancreatic cancer include cigarette smoking, type 2 diabetes, chronic pancreatitis, obesity, cirrhosis of the liver, and family history of pancreatic cancer.
In ~10% of cases, pancreatic cancers are “hereditary.” These cancers are often due to harmful genetic variants (differences), also known as mutations, that are inherited and are usually found in families with pancreatic and other cancers. Hereditary pancreatic cancer predisposition is due to a mutation that someone is born with.
Hereditary pancreatic cancer can be divided into the following categories: (1) hereditary cancer syndromes that include an increased risk for pancreatic cancer, (2) hereditary diseases that cause inflammation of the pancreas leading to an increased risk of pancreatic cancer, and (3) unknown genetic causes.
Hereditary Cancer Syndromes Associated with Pancreatic Adenocarcinomas
BRCA1 and BRCA2 Related Breast and Ovarian Cancer Syndrome
- Mutations in these genes can be inherited from either parent.
- Females with BRCA mutations have an increased risk for breast, ovarian, melanoma, and pancreatic cancer.
- Males with BRCA mutations have an increased risk for breast, prostate, melanoma, and pancreatic cancer.
- The lifetime risk for pancreatic cancer is thought to be ~2-3% (BRCA1) and ~2-5% (BRCA2); the majority of BRCA carriers will never develop pancreatic cancer.
- BRCA testing is now recommended for anyone with pancreatic adenocarcinoma.
PALB2 Gene Mutations
- Mutations in this gene can be inherited from either parent.
- PALB2 mutations are associated with an increased risk for pancreatic and female breast cancers (up to 58% lifetime risk) and perhaps male breast and other cancers.
- The exact pancreatic cancer risks associated with PALB2 mutations are not well defined at this time.
- Mutations in the PALB2 gene have been identified in ~1-3% of familial breast cancer cases and ~3-4% of familial pancreatic cancer cases.
Melanoma-Pancreatic Cancer Syndrome (M-PCS)
- M-PCS is a condition caused by certain mutations in the CDKN2A gene.
- Mutations in this gene can be inherited from either parent.
- The main cancer risk in M-PCS is the development of early, and often multiple, cases of melanoma; the risk may be as high as 76% by age 80.
- The lifetime risk of pancreatic cancer is thought to be as high as 17% in M-PCS.
- Caused by mutations in the MLH1, MSH2, MSH6, PMS2, or EPCAM genes that can be inherited from either parent.
- Individuals with Lynch syndrome have increased risks to develop colon, uterine, ovarian, other gastrointestinal cancers such as pancreatic cancer, urinary tract cancers, and specific skin findings that can be cancerous (sebaceous adenomas and carcinomas).
- The lifetime risk for pancreatic cancer is thought to be ~1-6% (MLH1), ~4% (MSH2), and slightly increased (MSH6, PMS6, or EPCAM).
Peutz-Jeghers Syndrome (PJS)
- Caused by mutations in the STK11 gene that can be inherited from either parent or can be the result of a new (de novo) mutation in ~25-45% of individuals with PJS.
- Children and young adults with PJS often have distinctive hyperpigmented spots on their lips, mouth, hands, and feet that look like freckles and fade beginning in puberty.
- Individuals with PJS have an increased risk of developing polyps throughout the GI tract and an ~85% lifetime risk of developing certain types of cancer.
- The lifetime risk for pancreatic cancer is 11-36%.
- Mutations in several other genes have been linked with increased risk of pancreatic cancer, including genetic mutations in TP53 (Li-Fraumeni syndrome), ATM, and APC (familial adenomatous polyposis syndrome).
Hereditary Cancer Syndromes Associated with Neuroendocrine Pancreatic Tumors
Von Hippel-Lindau (VHL)
- VHL is characterized by the development of cancerous and benign tumors that arise from the lining of blood vessels (hemangioblastomas).
- Individuals with VHL have an increased risk of developing neuroendocrine pancreatic tumors.
- The VHL gene has a relatively high rate of new (de novo) mutations, meaning that the mutation occurs for the first time in that individual, which may explain why features of this syndrome are often not seen in previous generations.
Multiple Endocrine Neoplasia Type 1 (MEN1)
- Caused by mutations in the MEN1 gene.
- This syndrome leads to an increased risk of tumors in some of the body’s hormone-producing glands, called endocrine glands; these tumors can be noncancerous or cancerous.
- The most common endocrine glands affected in MEN1 are the parathyroid glands, the pituitary gland, and the pancreas.
Hereditary Diseases Associated with an Increased Risk of Pancreatic Cancer
Hereditary Pancreatitis (HP)
- Primarily due to mutations in the PRSS1 gene that can be inherited from either parent.
- Mutations in other genes (SPINK1, CFTR, and CTRC) have also been linked to HP.
- Pancreatitis is recurring inflammation of the pancreas that can gradually cause damage to the pancreas and surrounding tissue.
- Clinical features of HP include recurrent pancreatitis, often beginning in the teenage years, leading to chronic pancreatitis in late adolescence to early adulthood.
- This chronic inflammation of the pancreas leads to increased risk of pancreatic cancer; lifetime risk of pancreatic cancer is estimated to be 25-40%.
- Smoking is associated with a further increase in risk and younger age of onset of pancreatic cancer.
- HP is rare and accounts for a small percentage of pancreatic cancer cases.
Cystic Fibrosis (CF)
- Due to mutations in the CFTR gene.
- An individual with CF has two CFTR mutations, one inherited from each parent.
- CF is characterized by lung disease and a lack of pancreatic digestive enzymes (pancreatic insufficiency).
- Patients with CF may have a ~5-7% risk of pancreatic cancer.
Unknown Genetic Causes
- While the above genetic syndromes account for ~20% of familial pancreatic cancer, it is clear there are other, undiscovered familial pancreatic cancer genes (e.g., relatives of patients with pancreatic cancer have an increased risk for developing pancreas cancer themselves).
- With one close relative who has had pancreatic cancer, the risk for pancreatic cancer increases from 1-2% to 4-6%. This estimated risk is unchanged with two affected relatives; however, in the presence of three or more closely related family members, the risk for pancreatic cancer has been estimated to be as great as 17-32%.
Referral for Genetic Counseling
BRCA testing is now recommended for any person who is diagnosed with pancreatic adenocarcinoma.
A referral to genetic counseling for hereditary pancreatic cancer should especially be considered for individuals with a personal and/or family history that includes any of the following risk factors:
- Multiple cases of pancreatic cancer on the same side of the family.
- A combination of related cancers on the same side of the family (e.g., pancreatic/breast/ovarian, pancreatic/melanoma, or pancreatic/colon/uterine/ovarian).
- Multiple related primary cancers in one individual (e.g., pancreatic/melanoma, pancreatic/breast).
- Ashkenazi Jewish ancestry and pancreatic cancer.
- Pancreatic cancer and multiple and/or early onset gastrointestinal polyps, including greater than 15 gastrointestinal polyps or greater than 5 hamartomatous polyps.