Pancreatic adenocarcinoma is a leading cause of cancer death. Few patients are candidates for curative resection due to the late stage at diagnosis. While most pancreatic adenocarcinomas are sporadic, approximately 10% have an underlying hereditary basis. Known genetic syndromes account for only 20% of the familial clustering of pancreatic cancer cases. The majority are due to non-syndromic aggregation of pancreatic cancer cases or familial pancreatic cancer. Screening aims to identify high-risk lesions amenable to surgical resection. However, the optimal interval for screening and the management of pancreatic cancer precursor lesions detected on imaging are controversial.
Key points
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Approximately 10% of pancreatic cancer cases are estimated to have an underlying hereditary basis. Of these, only 20% are caused by a known genetic syndrome. Most are caused by nonsyndromic aggregation of pancreatic cancer cases or familial pancreatic cancer.
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Assessment of family cancer history is essential to identify individuals who may benefit from genetic evaluation, testing for underlying cancer susceptibility genes, and screening for pancreatic cancer.
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Screening aims to identify preinvasive lesions with high-grade neoplastic changes that are significantly associated with an increased risk for invasive pancreatic cancer (pancreatic intraepithelial neoplasia-3 and intraductal papillary mucinous neoplasm with high-grade dysplasia).
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Endoscopic ultrasonography and MRI/magnetic resonance cholangiopancreatography can detect pancreatic cancer precursor lesions in high-risk individuals but have limitations.
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Novel biomarkers have the potential to inform the diagnosis and management of pancreatic cancer precursor lesions detected on imaging.
Introduction
Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States and the eighth leading cause worldwide. Surgical resection is the only potentially curative treatment of exocrine pancreatic cancer. However, because of the late presentation at diagnosis, only 15% to 20% of patients are candidates for surgery. Early detection of pancreatic cancer with curative resection can improve survival. Population-based screening for pancreatic cancer is not cost-effective given the low incidence of pancreatic cancer and the low positive predictive value of current screening modalities. However, individuals at increased risk for pancreatic cancer may benefit from screening to detect early pancreatic neoplasia and screening may be cost-effective.
Introduction
Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States and the eighth leading cause worldwide. Surgical resection is the only potentially curative treatment of exocrine pancreatic cancer. However, because of the late presentation at diagnosis, only 15% to 20% of patients are candidates for surgery. Early detection of pancreatic cancer with curative resection can improve survival. Population-based screening for pancreatic cancer is not cost-effective given the low incidence of pancreatic cancer and the low positive predictive value of current screening modalities. However, individuals at increased risk for pancreatic cancer may benefit from screening to detect early pancreatic neoplasia and screening may be cost-effective.
Epidemiology
Approximately 10% of pancreatic cancer cases are estimated to have an underlying hereditary basis. Of these, only 20% are caused by a known genetic syndrome ( Table 1 ).
| Syndrome | Gene | Estimated Lifetime Risk of Pancreatic Cancer (%) |
|---|---|---|
| Peutz-Jeghers syndrome | STK11 | 11–36 |
| FAMMM | p16/CDKN2A | 10–17 |
| Hereditary breast and ovarian cancer | BRCA2 | 5 |
| BRCA1 | 3.6 | |
| Fanconi anemia, breast cancer | PALB2 | Unknown |
| Lynch syndrome | MLH1 , MSH2 , MSH6 , PMS2 , EPCAM | 3.7 |
| Li-Fraumeni syndrome | p53 | Unknown |
| Familial adenomatous polyposis | APC | 2 |
| Ataxia-telangiectasia | ATM | Unknown |
| Hereditary pancreatitis | PRSS1 | 40 |
| Familial pancreatic cancer | Majority unknown | |
| 1 FDR | 6 | |
| 2 FDR | 8–12 | |
| ≥3 FDR | 40 |
Familial Pancreatic Cancer
Familial pancreatic cancer (FPC) has been defined by consensus opinion as affecting families with at least 2 first-degree relatives (FDRs) with pancreatic cancer without a known pancreatic cancer–associated hereditary syndrome.
The risk of pancreatic cancer in FPC families increases with the number of affected FDRs. Other important determinants of pancreatic cancer risk in FPC families include the age at pancreatic cancer diagnosis, the family size, and the number of first-degree relatives with pancreatic cancer in the family. Genetic anticipation has been noted in 65% to 80% of individuals from FPC families. In one prospective study that included 838 FPC kindreds, individuals with 1 affected FDR had a 4.5-fold increased risk compared with the general population. Those with 2 and 3 or more affected FDRs with pancreatic cancer had a 6.4-fold and 32-fold increased risk of developing pancreatic cancer, respectively.
Segregation models suggest that pancreatic cancer in FPC families may be caused by an autosomal dominant susceptibility gene with reduced penetrance, carried by approximately 7 per 1000 individuals. Initial studies also suggested that germline BRCA2 mutations may be found in 15% to 17% of FPC kindreds with an incident pancreatic cancer. However, in larger cohort studies, deleterious BRCA2 mutations were detected in only 6% of moderate-risk and high-risk families. Mutations in the partner and localizer of the BRCA2 ( PALB2 ) gene and ataxia-telangiectasia mutated ( ATM ) gene have also been identified in FPC kindreds. However, the underlying susceptibility gene that explains most cases of pancreatic cancer caused by an inherited predisposition have not been identified.
The complexity in pancreatic cancer risk assessment has been the impetus for the development of a prediction model. The PancPRO model takes into account an individual’s age, personal and family history of cancer, age at cancer diagnosis, and family size, and can provide a quantitative estimate of the absolute lifetime pancreatic cancer risk without knowing the gene responsible for the aggregation of pancreatic cancer in a family.
Pancreatic Cancer Associated with Inherited Cancer Syndromes
Peutz-Jeghers syndrome
Peutz-Jeghers syndrome (PJS) is an autosomal dominant hamartomatous polyposis syndrome with high penetrance caused by a mutation in the STK11 gene. PJS is characterized by multiple hamartomatous polyps and mucocutaneous pigmentation. Hamartomatous polyps can develop throughout the gastrointestinal tract but most commonly occur in the small bowel. Gastrointestinal polyps usually develop in the first decade of life and most patients are symptomatic by the age of 30 years. Hamartomatous polyps can also occur in the urinary bladder, renal pelvis, nasopharynx, and lungs. More than 95% of individuals with PJS have mucocutaneous pigmentation that develops early in life and then fades after puberty, with the exception of lesions on the buccal mucosa.
Individuals with PJS have an estimated lifetime risk of pancreatic cancer of 11% to 36%, with a mean age of 41 years at pancreatic cancer diagnosis. PJS is also associated with an increased risk for colorectal, gastric, and small bowel cancers, with lifetime risks of 39%, 29%, and 13%, respectively. In addition, individuals with PJS are at an increased risk for cancers of the breast, ovary, cervix, uterus, testicle, and lung. A clinical diagnosis of PJS requires the presence of any one of the following: 2 or more histologically confirmed Peutz-Jeghers (PJ) polyps; any number of PJ polyps in an individual who has a family history of PJS in a close relative; characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in a close relative; or any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation. Genetic testing for mutation in the STK11 gene in an individual who meets clinical criteria for PJS serves to establish the diagnosis of PJS.
Familial atypical multiple mole and melanoma
Familial atypical multiple mole and melanoma (FAMMM) is an autosomal dominantly inherited syndrome caused by mutations in the CDKN2A gene. The CDKN2A gene encodes the p16 protein, which functions as a cell cycle regulator. FAMMM is characterized by multiple melanocytic nevi, atypical melanocytic nevi, and an increased risk for early onset melanoma. Individuals with a clinical diagnosis of FAMMM have a 13-fold to 22-fold increased risk of pancreatic cancer compared with the general population. In individuals with the Leiden founder mutation in the CDKN2A gene, the risk of pancreatic cancer is increased 47-fold. Individuals with FAMMM are also at an increased risk for cancer of the respiratory tract, eye/brain, oropharynx, and nonmelanoma skin cancer.
Hereditary breast cancer
Hereditary breast and ovarian cancer syndrome is characterized by early onset breast and/or ovarian cancer caused by autosomal dominant, highly penetrant, germline mutations in BRCA1 and BRCA2 . Individuals with germline mutations in BRCA2 have a 3.5-fold to 5.9-fold increased risk of developing pancreatic cancer, with a mean age of 63 years at diagnosis. Germline BRCA2 mutations account for the highest proportion of known causes of inherited pancreatic cancer. BRCA2 mutations have been found in 6% to 17% of tested FPC kindreds with an incident pancreatic cancer. It is estimated that 1.7% to 10% of patients of Ashkenazi Jewish ancestry with pancreatic cancer carry a BRCA mutation and most these patients lack a family history of BRCA -associated cancers.
Individuals with germline mutations in BRCA1 have a lower risk of pancreatic adenocarcinoma compared with those with a BRCA2 mutation. In one cohort study that included 11,847 individuals from 699 families segregating a BRCA1 mutation, the risk of pancreatic cancer was increased 2-fold compared with the general population. However, patients were ascertained for young age of onset of breast and/or ovarian cancers and estimates of cancer risk may be lower in FPC families ascertained through pancreatic cancer probands.
Approximately 1% of hereditary breast cancers are caused by germline mutations in the PALB2 gene. The PALB2 protein binds with the BRCA2 protein and stabilizes key nuclear structures needed for DNA repair. Mutations in the PALB2 gene confer an increased risk of both breast and pancreatic cancer and have been identified in 2% to 5% of FPC families. Although the absolute risk for pancreatic cancer in individuals with a PALB2 mutation is unknown, given the similarities in gene function of PALB2 and the BRCA genes, the risk of pancreatic cancer is likely to be comparable.
Lynch syndrome
Lynch syndrome or hereditary nonpolyposis colorectal cancer is caused by germline mutations in mismatch repair genes MLH1 , MSH2 , MSH6 , or PMS2 , or deletions in the EPCAM gene that result in downstream promotor hypermethylation and silencing of MSH2 . Lynch syndrome is the most common inherited familial colorectal cancer syndrome and is characterized by early onset colorectal cancer with a lifetime risk of 60% to 80%. Individuals with Lynch syndrome are at an increased risk for cancers of the endometrium, ovary, stomach, small bowel, urinary tract, and brain. The risk of pancreatic cancer in individuals with Lynch syndrome is increased 9-fold to 11-fold compared with the general population. Pancreatic adenocarcinomas in patients with Lynch syndrome characteristically show medullary histology with microsatellite instability and loss of expression of mismatch repair proteins. In one study that evaluated 47 pancreatic cancer cases from 31 families with Lynch syndrome, the cumulative risk of pancreatic cancer in individuals with Lynch syndrome was 1.3% by age 50 years and 3.7% by age 70 years.
Li-Fraumeni syndrome
Li-Fraumeni syndrome (LFS) is an inherited autosomal dominant disorder caused by a germline mutation in the tp53 tumor suppressor gene. LFS is characterized by early onset breast cancer, sarcomas, adrenocortical carcinoma, and brain tumors. Individuals with a tp53 mutation also have a 7-fold increased risk of pancreatic cancer compared with the general population.
Familial adenomatous polyposis
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by mutations in the APC gene, which encodes a protein that functions as a tumor suppressor and regulates the Wnt pathway. In the classic form of FAP, patients have hundreds or thousands of adenomatous polyps that typically develop during adolescence. A milder, attenuated form of FAP is characterized by fewer than 100 adenomas that are diagnosed at a later age (mean age of 44 years). In the absence of intervention, individuals with FAP have a nearly 100% risk of developing colorectal cancer in their lifetime. They are also at increased risk of extracolonic cancers, including duodenal and thyroid cancer, childhood hepatoblastoma, and central nervous system tumors. There are limited data with regard to the risk of pancreatic cancer in individuals with FAP. However, in one study, individuals with FAP had a 4.5-fold increased risk for pancreatic adenocarcinoma compared with the general population with an absolute lifetime risk of approximately 2%.
Ataxia-telangiectasia
Ataxia-telangiectasia is caused by biallelic deleterious mutations in the ATM gene. The ATM protein is a serine/threonine kinase involved in DNA repair. Ataxia-telangiectasia is characterized by ataxia, oculocutaneous telangiectasias, radiation sensitivity, immune deficiency, and an increased incidence of malignancy. Monoallelic mutations in the ATM gene are associated with a 3-fold increased risk of pancreatic cancer and are found in 2.4% of FPC families.
Hereditary pancreatitis
Hereditary pancreatitis is characterized by chronic pancreatitis caused by recurrent attacks of acute pancreatitis. Hereditary pancreatitis is associated with mutations in the PRSS1 gene, which encodes cationic trypsinogen. The 2 most common mutations in PRSS1 , R122H and N29I, have a high penetrance.
Normally, cationic trypsinogen is secreted by the pancreas into the duodenum where it is ultimately cleaved into trypsin, which in turn aids proteolysis. Mutations in PRSS1 result in premature activation of trypsinogen resulting in pancreatic inflammation and pancreatitis. Most affected individuals develop symptoms before age 20 years and often before the age of 5 years. Individuals with hereditary pancreatitis have a 53-fold increased risk of pancreatic cancer compared with the general population. The estimated lifetime risk of pancreatic cancer in individuals with hereditary pancreatitis is 40%, with an average age of 57 years at pancreatic cancer diagnosis.
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