Last Updated November 2018
In recognition of Pancreatic Cancer Awareness Month, we’ve compiled information about inherited forms of pancreatic cancer.  This is the second installment of our series, check out the first installment.
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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. We covered Category 1 in a previous post.  In this post, we will discuss Categories 2 and 3 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
3. Unknown Genetic Causes

Hereditary Diseases Associated with an Increased Risk of Pancreatic Cancer

Hereditary Pancreatitis (HP)
 Photo Credit: ISCN 2009 Photo Credit: ISCN 2009

  • 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 with 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 PC
  • 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 2 CFTR mutations, one inherited from each parent.
  • CF is characterized by lung disease and the lack of enough 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 that there are other, undiscovered familial pancreatic cancer genes. For example, 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. See out the first installment for details.
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.

NCCN 1.2019
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