The Genetics of Pancreatic Cancer: Part 1

In recognition of Pancreatic Cancer Awareness Month we’ve compiled information about inherited forms of pancreatic cancer. 

Photo Credit: chamberlain.edu

Photo Credit: chamberlain.edu

As you may know, 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 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 inherited genetic changes and are usually found in families with pancreatic and other cancers.  Hereditary pancreatic cancer is due to inherited genetic causes that people are born with (these gene changes do not develop over time).

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

3. Unknown Genetic Causes

 

1).  Hereditary Cancer Syndromes

a. Pancreatic cancers, usually adenocarcinomas

                   i. BRCA1 and BRCA2 -Related Breast and Ovarian Cancer Syndrome

Photo Credit: Wikipedia

Photo Credit: Wikipedia

  • 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.
  • BRCA2 mutations have been identified in ~17-19% of familial pancreatic cancer families (even in the absence of a family history of breast and/or ovarian cancer), ~7% of apparently sporadic pancreatic cancers and ~10% of Ashkenazi Jewish individuals with pancreatic cancer.

ii. PALB2 gene

Photo Credit: Wikipedia Commons

Photo Credit: Wikipedia Commons

  • 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 and perhaps male breast cancer. The exact cancer risks associated with PALB2 mutations are not well defined at this time.
  • Germline 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) and Melanoma Cancer Syndrome (MCS)
  • M-PCS is a condition caused by a mutation in the CDKN2A gene.
  • MCS is a condition caused by a mutation the CDKN2A or CDK4 gene.
  • Mutations in these genes can be inherited from either parent.
  • The main cancer risk in both M-PCS and MCS 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 and still being studied in MCS.
    • 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.

                   v.     Peutz-Jeghers Syndrome (PJS)

Photo Credit: proteopedia.org

Photo Credit: proteopedia.org

  • 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 into adulthood.
  • 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%.
  • Pancreatic cancer screening for individuals with PJS includes magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) every 1-2 years starting between the ages of 30-35 years. This screening should be performed in an experienced center using a multidisciplinary approach.
  • PJS is a rare condition.

                 vi.     Other Genes

  • Other genes including APC, SMAD4, BMPR1A and TP53 have also been associated with slight increased risk for pancreatic cancers
  • Individuals with a ‘classic’ APC mutation generally develop 10-100s of colon polyps and have a significantly increased risk to develop colorectal cancer without preventive surgery. 
  • Some individuals with SMAD4 and BMPR1A mutations have an increased risk to develop juvenile polyps and other cancers, including pancreatic cancer.
  • Individuals with a TP53 mutation have significantly increased risks for breast cancer, sarcomas, brain tumors, adrenocortical carcinomas and other cancers in their lifetime.  These risks may include pancreatic cancer.

b. Pancreatic cancers, usually neuroendocrine tumors

i. Von-Hippel Lindau (VHL)

Photo Credit: Wikipedia

Photo Credit: Wikipedia

  • Individuals with VHL are characterized by the development of cancerous and benign tumors that are made up of newly formed 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.

           

ii. 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 two or more 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.

           iii. Neurofibromatosis Type 1 (NF1)

ISCN 2009

ISCN 2009

  • Caused by mutations in the NF1 gene.
  • This syndrome leads to an increased risk of many tumors, changes in skin coloring (pigmentation) and the growth of tumors along nerves in the skin, brain, and other parts of the body. The signs and symptoms of this condition vary widely among affected people.
  • The risk for a rare type of pancreatic tumor (somatostatinoma) is increased.

Referral for Genetic Counseling:

A referral to genetic counseling for hereditary pancreatic cancer should 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. 

 

References

NCCN 1.2017

Petrucellil, 2013. 

Rebbeck 2005.

Eisen 2008.

Iodice 2010.

Olopade 2004.

Solomon 2012.

SEER Stat Fact Sheets: Pancreas.

Greer 2009.

Lynch 2011.

Engel 2012. 

NCCN 2.2016

Kohlman and Gruber 2014.

NCCN 1.2017

Syngal 2015.

Samadder 2015.

NCCN Guidelines, Version 2.2015

Salo-Mullen 2015