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July 2016
Hereditary Pancreatic Cancer
The lifetime risk of pancreatic cancer among men and women in the United States is ~1.4% and
most cases of pancreatic cancers are sporadic (1). However, an estimated 10% of cases may be
due to an underlying hereditary cause (2,3). Although our knowledge and the genetic testing
options for hereditary pancreatic cancer have increased in recent years, the underlying genetic
cause for clusters of pancreatic cancer in many families is still unclear.
Hereditary pancreatic cancer can be divided into several distinct categories: 1) known
hereditary cancer syndromes mainly defined by risk for other cancers which include an
increased risk of PC; 2) known hereditary disease which causes inflammation of the pancreas
leading to an increased risk of PC; 3) familial pancreatic cancer (a clustering of pancreatic
cancer in 2 or more first degree relatives) in which the underlying genetic cause is not yet
known (4).
Genetic testing is available for the following:
Hereditary Cancer Syndromes
Hereditary Breast and Ovarian Cancer (HBOC)
HBOC is caused by mutations (genetic changes) in the BRCA1 and BRCA2 genes and is
associated with significantly increased risks of breast, ovarian, and prostate cancer. Mutations
in the BRCA2 gene are the most common genetic cause for familial pancreatic cancer.
Individuals with BRCA2 mutations have a 4-8% lifetime risk to develop pancreatic cancer.
Familial Atypical Multiple Mole Melanoma Syndrome (FAMMM)
FAMMM is caused by mutations in the CDKN2A (p16) gene (2,3). Individuals with a CDKN2A
mutation develop multiple moles (including many that are atypical or “dysplastic”) and have an
increased risk of developing melanoma including melanoma at an earlier than average age and
multiple melanomas. CDKN2A mutations are associated with a ~10-19% lifetime risk of PC
(2,3,4,7).
Familial adenomatous polyposis (FAP)
FAP is caused by mutations in the APC gene and is associated with the development of 100s to
1000s of colon polyps and an almost 100% risk of developing colorectal cancer if risk reducing
surgery is not performed. Individuals with FAP also have an increased risk to develop
osteomas, fibromas, a benign eye finding known as CHRPE, desmoid tumors, and polyps/cancer
in the small bowel or stomach. Individuals with FAP have a 2-4% increased risk to develop
pancreatic cancer.
Smilow Cancer Genetics and Prevention
330 Orchard Street, Suite 107
New Haven, CT 06510
Phone: 203-200-4362
Fax:
203-200-1362
[email protected]
http://yalecancercenter.org/patient/specialty/genetics/
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Lynch Syndrome/ Hereditary Non-polyposis Colorectal Cancer (HNPCC)
Lynch syndrome is caused by mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes
(3,12). Individuals with Lynch syndrome have a significantly increased risk of developing colon,
uterine and ovarian cancer as well as some increased risk to develop other gastrointestinal,
urinary tract cancers and sebaceous skin cancers. The link between pancreatic cancer and
Lynch syndrome is less clear but recent data suggest that individuals with Lynch syndrome may
have a ~3-4% lifetime risk of PC (3,12).
Peutz-Jeghers Syndrome (PJS)
PJS is a rare hereditary cancer syndrome involving multiple polyps throughout the
gastrointestinal tract, dark blue to brown spots or “freckling” on the lips, hands, feet, and in the
mouth, and increased risk for cancers within and outside of the gastrointestinal tract (e.g.
colorectal, breast, gynecologic, stomach) (2,3). Individuals with PJS have a lifetime risk of ~1136% to develop PC (2,3).
PALB2 gene/ATM gene
Mutations in the PALB2 gene and ATM gene are associated with an increased risk of pancreatic
and female breast cancers. These genes have been identified and studied more recently, so the
risks for other types of cancers and the exact cancer risks are not well defined at this time
(9,10,11).
Hereditary Diseases Associated with an Increased Risk of Pancreatic Cancer
Hereditary Pancreatitis (HP)
HP is a rare genetic disease characterized by recurrent episodes of severe pancreatitis
(inflammation of the pancreas), often beginning in the teenage years, and leading to chronic
pancreatitis in late adolescence to early adulthood (2,3). HP is primarily due to mutations in the
PRSS1 (cationic trypsinogen) gene or SPINK1 gene (2,3).
Individuals with hereditary
pancreatitis have a ~25-40% lifetime risk of PC (2,3) Smoking is associated with a further
increase in risk and younger age of onset of PC (2,3).
Cystic Fibrosis (CF)
CF is a genetic disease that is due to mutations in the CFTR gene and is characterized by chronic
obstructive lung disease and pancreatic insufficiency (2). Individuals with CF may have an
increased risk of pancreatic cancer and may be diagnosed at young ages (2).
Referral for Genetic Counseling:
Consider being evaluated by a genetic counselor if you have a personal and/or family history
that includes any of the following:
• 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)
Smilow Cancer Genetics and Prevention
330 Orchard Street, Suite 107
New Haven, CT 06510
Phone: 203-200-4362
Fax:
203-200-1362
[email protected]
http://yalecancercenter.org/patient/specialty/genetics/
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
Multiple related new 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
Screening for Individuals at Increased Risk:
Routine population screening for pancreatic cancer is not useful due the limitations of the
available screening and the fact that pancreatic cancer is rare (2,3). However, some data
suggest that screening may prove valuable in individuals at high risk by detecting cancers at an
earlier, treatable stage (2,3). The optimal screening method for pancreatic cancer is still unclear
due to the risks and limitations of each of the available methods. However, consideration of
screening, particularly in the setting of a research study, is recommended for individuals with a
significantly increased risk to develop pancreatic cancer. We provide referrals for appropriate
individuals to discuss pancreatic cancer screening and clinical trial options with our pancreatic
experts.
Please contact the Smilow Cancer Genetics and Prevention Program at 203-200-4362 if you
would like further information or to schedule an appointment.
Smilow Cancer Genetics and Prevention
330 Orchard Street, Suite 107
New Haven, CT 06510
Phone: 203-200-4362
Fax:
203-200-1362
[email protected]
http://yalecancercenter.org/patient/specialty/genetics/
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References:
1. SEER Stat Fact Sheets: Pancreas. Retrieved August 9, 2011 from
http://seer.cancer.gov/statfacts/html/pancreas.html .
2. Greer JB, Lynch HT, and Brand RE (2009). Hereditary pancreatic cancer: A clinical perspective.
Best Practice and Research Clinical Gastroenterology 23:159-170.
3. Gover S and Syngal S (2010). Hereditary pancreatic cancer. Gastroenterology 139:1076-1080.
4. Reider H and Bartsch DK (2004). Familial pancreatic cancer. Familial Cancer 3:69-74.
5. Petrucelli N et al (2011) BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. Retrieved
August 16, 2011 from http://www.ncbi.nlm.nih.gov/books/NBK1247/ .
6. Murphy KM et al (2002). Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and
BRCA2 in familial pancreatic cancer: Deleterious BRCA2 mutations in 17%.Cancer Research
62:3789-3793.
7. Habbe N et al (2006). Familial pancreatic cancer syndromes. Endocrinology and Metabolism
Clinics of North America 35:417-430.
8. Kim DH et al (2009). Prevalence and characteristics of pancreatic cancer in families with
BRCA1 and BRCA2 mutations. Familial Cancer 8:153-158.
9. Hofstatter EW et al (2011). PALB2 mutations in familial breast and pancreatic cancer. Familial
Cancer 10:225-231.
10. Tischkowitz M and Bing X (2010). PALB2/FANCN: Recombining cancer and Fanconi Anemia.
Cancer Research 70(19):7353-7359.
11. Casadei S et al (2011). Contribution of inherited mutations in the BRCA2-interacting protein
PALB2 to familial breast cancer. Cancer Research 71(6):2222-2229.
12. Kastrinos F et al (2009). Risk of pancreatic cancer in families with Lynch Syndrome. JAMA
302(16):1790-1795.
nd
13. Schneider K (2002). Counseling About Cancer, 2 edition. New York: Wiley-Liss, Inc.
14. Amos CI et al (2011) Peutz-Jeghers Syndrome. Retrieved August 16, 2011 from
http://www.ncbi.nlm.nih.gov/books/NBK1266/ .
15. Moskowitz SM et al (2011). CTFR-related disorders. Retrieved August 16, 2011 from
http://www.ncbi.nlm.nih.gov/books/NBK1250/ .
16. Roberts NJ et al (2012). ATM mutations in hereditary pancreatic cancer patients. Cancer
Discov. 2(1): 41-46.
17. Ghiorzo P et al (2014). Genetic predisposition to pancreatic cancer. World J Gastroenterol.
20(31): 10778-10789.
18. Ashton C and Gallinger S. (2015). Hereditary pancreatic cancer syndromes. Surg Oncol Clin
N Am 24: 733-764.
Smilow Cancer Genetics and Prevention
330 Orchard Street, Suite 107
New Haven, CT 06510
Phone: 203-200-4362
Fax:
203-200-1362
[email protected]
http://yalecancercenter.org/patient/specialty/genetics/