Last Updated November 2018
In recognition of Pancreatic Cancer Awareness Month, we’ve compiled information about hereditary forms of pancreatic cancer.
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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 three categories below. In this post, we will discuss Category 1 below:
1. Hereditary Cancer Syndromes that include an increased risk for pancreatic cancer

a. Pancreatic cancers, adenocarcinomas

b. Pancreatic cancers, neuroendocrine tumors

2. Hereditary Disease that causes inflammation of the pancreas, leading to an increased risk of pancreatic cancer
3. Unknown Genetic Causes

Hereditary Cancer Syndromes associated with pancreatic adenocarcinomas

BRCA1 and BRCA2 -Related Breast and Ovarian Cancer Syndrome
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  • Mutations in these genes can be inherited from either parent.
  • Females with BRCA mutations have increased risks for breast, ovarian, melanoma and pancreatic cancer.
  • Males with BRCA mutations have increased risks for breast, prostate, melanoma and pancreatic cancer.
  • The lifetime risk for pancreatic cancer in thought to be ~ 2-3% (BRCA1) and ~2-5% (BRCA2). Therefore the vast majority of BRCA carriers will never develop pancreatic cancer.
  • BRCA testing is now recommended for any person with pancreatic adenocarcinoma.

PALB2 gene mutations
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  •  Mutation in this gene can be inherited from either parent.
  • Mutations in the PALB2 gene are associated with an increased risk of 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 for the development of early, and often multiple, cases of melanoma. The risk may be as high as 76% by age 80 years of age.
  • The lifetime risk of pancreatic cancer is thought to be as high as 17% in M-PCS

Lynch Syndrome

  • 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), depending on the gene involved.

Peutz-Jeghers Syndrome (PJS)
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  • Caused by mutations within the STK11 gene that can be inherited from either parent, or 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 ~85% lifetime risk of developing certain types of cancer.
  • The lifetime risk for pancreatic cancer is 11-36%.

   Other Genes

  • Mutations in several other genes have been linked with increased risk of pancreatic cancer, including mutations in the  TP53 gene (Li-Fraumeni syndrome), ATM, and APC (familial adenomatous polyposis syndrome).

Hereditary Cancer Syndromes most often associated with neuroendocrine pancreatic tumors

Von Hippel-Lindau (VHL)
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  • VHL is characterized by the development of cancerous and benign tumors that arise from the lining of blood vessels (hemangioblastomas).
  • Individuals with VHL also have an increased risk to develop 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.  This may explain why features of this syndrome are often not seen in previous generations.

Multiple Endocrine Neoplasia Type 1 (MEN1)
 ISCN 2009 ISCN 2009

  • 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.

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.

Please check back for our Part 2 series for information on Hereditary Diseases Associated with an Increased Risk of Pancreatic Cancer and Unknown Genetic Causes of Pancreatic Cancer.


NCCN 2.2019
Petrucellil, 2013. 
Rebbeck 2005.
Eisen 2008.
Iodice 2010.
Olopade 2004.
Solomon 2012.
SEER Stat Fact Sheets: Pancreas.
Greer 2009.
Lynch 2011.
Engel 2012. 
Kohlman and Gruber 2014.
Syngal 2015.
Samadder 2015.
NCCN Guidelines, Version 1.2018
Salo-Mullen 2015