Familial pancreatic cancer (FPC) kindreds have at least 2 first-degree relatives with pancreatic ductal adenocarcinoma. Studies of FPC have focused on the discovery of genetic cause and on the management of those at genetically high risk. Research reveals that a half dozen known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the most prominent of which are BRCA2 and CDKN2A . Genetic risk assessment and testing is already available. Owing to limited experience worldwide, guidance is often based on expert opinion, although all agree that research is needed to improve the shaping of options.
Key points
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Familial pancreatic cancer (FPC) kindreds have 2 or more first-degree relatives ever diagnosed with pancreatic ductal adenocarcinoma.
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Patients with FPC constitute 8% to 10% of all patients with pancreatic cancer. Positive family history of pancreatic cancer is a consistent risk factor, with twofold increased risk to first-degree relatives.
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Although novel genes that predispose to FPC remain to be discovered, increased risk of pancreatic cancer is now known to be associated with half a dozen inherited syndromes with known germline mutations, including BRCA1, BRCA2, CDKN2A, PALB2, ataxia telangiectasia mutated ( ATM) , mismatch repair genes, as well as PRSS1 and SPINK2 of hereditary pancreatitis.
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Predisposition genetic testing for individuals in FPC kindreds is feasible and typically consists of sequencing a panel of multiple genes. Cancer risk assessment is less precise, and research into prevention and screening is nascent.
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Guidelines for management of family members at risk for FPC are being developed or disseminated. Owing to limited experience worldwide, guidance is often based on expert opinion. It is agreed that more research is needed to improve the shaping of options.
Introduction
Pancreatic cancer is a devastating diagnosis for patients and their families, and it is the fourth leading cause of cancer death. Among the major cancers, pancreatic cancer has the worst survival and historically, has been the least studied. Approximately 95% of pancreatic neoplasms are ductal adenocarcinomas. The rapid mortality of patients with pancreatic adenocarcinoma makes this cancer challenging for research into basic, translational, and epidemiologic studies. For genetic or molecular investigations that require biospecimens for DNA studies, involving patients who are often too ill to participate and whose disease precludes surgical resection (with consequent lack of tumor tissue) has posed difficulties.
This longstanding dearth of knowledge has resulted in only minimal inroads to improve risk reduction or survival. In the United States, the incidence and mortality rates have remained largely unchanged since 1973. During 2005–2009, the incidence rate for whites and African Americans was 11.6 of 105 and 15.2 of 105, respectively. Mortality rates were 10.7 of 105 for whites and 13.8 of 105 for African Americans. The 5-year survival has been 4% to 6% for decades. The low survival from pancreatic cancer is primarily due to the advanced stage at diagnosis in most cases: by the time of diagnosis, 80% of pancreatic carcinomas are no longer localized to the pancreas. To date, no reliable screening tests or effective cures for pancreatic cancer are available; there are few long-term survivors.
It is crucial to advance the knowledge of etiology to enable evidence-based strategies to decrease incidence and mortality. For years, pancreatic cancer was thought to be a sporadic disease, due in part to the lack of systematic studies and the inherent challenges as described earlier. Over the past 2 decades, however, there has been sustained effort to elucidate its genetics. As demonstrated for a variety of cancers, genetic epidemiology and family-based approaches have led to important breakthroughs in a variety of diseases, and particularly cancer. Discerning familial patterns of cancer incidence, combined with detailed studies of clinical and DNA variation, has defined a variety of inherited cancer syndromes and their causal genes. This article reviews the evidence for a genetic component of pancreatic cancer, studies of hereditary syndromes that feature increased risk of pancreatic cancer, and the current status of clinical translation of the findings.
Introduction
Pancreatic cancer is a devastating diagnosis for patients and their families, and it is the fourth leading cause of cancer death. Among the major cancers, pancreatic cancer has the worst survival and historically, has been the least studied. Approximately 95% of pancreatic neoplasms are ductal adenocarcinomas. The rapid mortality of patients with pancreatic adenocarcinoma makes this cancer challenging for research into basic, translational, and epidemiologic studies. For genetic or molecular investigations that require biospecimens for DNA studies, involving patients who are often too ill to participate and whose disease precludes surgical resection (with consequent lack of tumor tissue) has posed difficulties.
This longstanding dearth of knowledge has resulted in only minimal inroads to improve risk reduction or survival. In the United States, the incidence and mortality rates have remained largely unchanged since 1973. During 2005–2009, the incidence rate for whites and African Americans was 11.6 of 105 and 15.2 of 105, respectively. Mortality rates were 10.7 of 105 for whites and 13.8 of 105 for African Americans. The 5-year survival has been 4% to 6% for decades. The low survival from pancreatic cancer is primarily due to the advanced stage at diagnosis in most cases: by the time of diagnosis, 80% of pancreatic carcinomas are no longer localized to the pancreas. To date, no reliable screening tests or effective cures for pancreatic cancer are available; there are few long-term survivors.
It is crucial to advance the knowledge of etiology to enable evidence-based strategies to decrease incidence and mortality. For years, pancreatic cancer was thought to be a sporadic disease, due in part to the lack of systematic studies and the inherent challenges as described earlier. Over the past 2 decades, however, there has been sustained effort to elucidate its genetics. As demonstrated for a variety of cancers, genetic epidemiology and family-based approaches have led to important breakthroughs in a variety of diseases, and particularly cancer. Discerning familial patterns of cancer incidence, combined with detailed studies of clinical and DNA variation, has defined a variety of inherited cancer syndromes and their causal genes. This article reviews the evidence for a genetic component of pancreatic cancer, studies of hereditary syndromes that feature increased risk of pancreatic cancer, and the current status of clinical translation of the findings.
Evidence for genetic basis of pancreatic cancer
Familial Clustering
Early reports of familial clusters of pancreatic cancer provided the first suggestion that at least a hereditary, but rare form of pancreatic cancer might exist. Reports of clusters included families in which multiple siblings were affected (but not the parents) or 1 family in which 3 generations contained an affected member each.
Familial Aggregation Studies and Analysis of Families
More formal study designs that apply epidemiologic and genetic segregation analysis methods are widely accepted standards to uncover existence of genetic basis for a cancer. One conventional approach to investigating potential host susceptibility is to perform case-control comparisons of family history of pancreatic cancer. A comprehensive summary of these studies and estimated risks are listed in Table 1 . Seven case-control studies, 2 cohort studies, 1 population-based genealogic analysis, and 1 case series that estimated the incidence of pancreatic cancer in relatives have found that first-degree relatives have at least a 2-fold increased risk of developing pancreatic cancer. These findings are remarkably consistent, given that case ascertainment and data collection spanned 30 or more years, multiple countries and cultures, and different methods for estimating risk. A systematic review and meta-analysis by Permuth-Wey and Egan of 1 cohort study and 7 case-control studies totaling 6568 pancreatic cancer cases calculated an overall relative risk of 1.80 (95% confidence interval [CI], 1.48–2.12). The investigators also found that 1.3% of pancreatic cancers in the population is attributable to family history. The risk was consistent for both males and females, and did not differ by early or late age at diagnosis. With respect to risk for second-degree relatives (aunts, uncles, grandparents, grandchildren), both Hassan and colleagues and Shirts and colleagues reported risks comparable to those of first-degree relatives (relative risks of 2.9 [95% CI, 1.3–6.3] and 1.59 [95% CI, 1.31–2.91], respectively). In addition, a large multicenter cohort study examined risk by number of affected individuals and showed high risk associated with having 2 or more first-degree relatives with pancreatic cancer with odds ratio (OR) of 4.26 (95% CI, 0.48–37.79).
| Location, Years of Study | Cases, N | Controls, N | Risk of Pancreatic Cancer in Family Members | Reference | |
|---|---|---|---|---|---|
| Risk | 95% CI | ||||
| Louisiana, 1979–1983 | 362 | 1408 | 5.25 | 2.1–13.2 | Falk et al, 1988 |
| Canada, 1984–1988 | 174 | 136 | 5.0 | 1.2–24.5 | Ghadirian et al, 2002 |
| Italy, 1983–1992 | 363 | 1234 | 2.8 | 1.3–6.3 | Fernandez et al, 1994 |
| United States, 1986–1989 | 484 | 2099 | 3.2 | 1.8–5.6 | Silverman et al, 1999 |
| Japan, cohort, 1988–1999 | 200 | 2200 | 2.09 | 1.01–4.33 | Inoue et al, 2003 |
| United States, 1996–1999 | 247 | 420 | 2.49 | 1.3–4.7 | Schenk et al, 2001 |
| Texas, 2000–2006 | 888 | 888 | 3.3 | 1.8–6.1 | Hassan et al, 2007 |
| United States, 2005–2009 | 654 | 697 | 2.79 | 1.44–4.08 | Austin et al, 2013 |
| International, PanScan Cohort Consortium (1 case-control and 10 cohort studies), 1985–2001 | 1183 | 1205 | 1.76 | 1.19–2.61 | Jacobs et al, 2010 |
| Utah, genealogy database, 1966–2010 | 1411 | — | RR = 1.84 | 1.47–2.29 | Shirts et al, 2010 |
| Minnesota, case series, 2000–2004 | 426 | — | SIR = 1.88 | 1.27–2.68 | McWilliams et al, 2005 |
The authors’ experience and those of the others has shown that 8% to 10% of patients with pancreatic adenocarcinoma report having had a first-degree relative (parent, sibling, or child) with pancreatic cancer. This proportion is congruent with family history patterns observed in series of patients with colorectal cancer, breast cancer, lung cancer, and prostate cancer. In addition, a population-based twin study of cancer in Sweden by Lichtenstein and colleagues estimated pancreatic cancer heritability to be 36%, similar to that of colorectal cancer (35%), higher than that of breast cancer (27%), and slightly lower than that of prostate cancer (42%). Taken together, this implies that pancreatic adenocarcinoma susceptibility patterns would be consistent with those seen for the more common cancers and it could be likewise expected that predisposition genes exist.
Segregation analysis is a statistical method that determines if a gene consistent with a mendelian inheritance pattern could cause the observed familial aggregation of a trait. Klein and colleagues analyzed family histories of 287 patients with pancreatic cancer seen from 1994–1999 at Johns Hopkins Hospital in Baltimore, MD, USA. The analysis rejected nongenetic transmission models. The data best fit a major gene model that was predicted to follow an autosomal dominant pattern of a rare allele; 0.7% of the population would carry a high risk of developing pancreatic cancer because of this putative gene. A smaller study of 70 families by Banke and colleagues arrived at a similar conclusion.
Familial Pancreatic Cancer Defined to Advance Research
Increased attention on the genetic analysis of pancreatic cancer required that a standard definition be applied so that research on risk factors and gene discovery in the familial setting would be consistent. In 1998, Hruban and colleagues proposed that FPC would be defined as kindreds containing at least a pair of individuals who were affected with pancreatic adenocarcinoma and who were first-degree relatives. This definition was simple, yet provided a sufficient boundary and is now widely used and facilitates a variety of studies. In particular, the multicenter Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium was formed to systematically collect risk factor and family history data plus germline DNA from blood or saliva from members of FPC kindreds. The resources would be used for gene discovery and genetic epidemiologic characterization. Many of the advances described here were enabled by the ongoing activities of the PACGENE Consortium members. To date, 44,183 patients at 7 sites have been screened for family history, of whom 3190 (7.2%) with positive family history have been enrolled, along with 7012 adult (99% unaffected) relatives of these patients.
Characteristics of familial pancreatic cancer: sex, incident risk, age at onset, smoking, other cancers
Based on the PACGENE data, approximately half of the patients with FPC are males, which is consistent with the proportion observed in sporadic pancreatic cancer. With respect to incident risk, family history studies described earlier clearly document the risk. Klein and colleagues analyzed 5179 individuals in 838 Johns Hopkins FPC kindreds and quantified risk using standardized incidence ratios (SIRs) that compared the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology, and End Results (SEER) rates. During the follow-up period from the time of enrollment, 19 pancreatic cancers developed among the relatives. The observed-to-expected rate of pancreatic cancer was 9.0 (95% CI, 4.5–16.1), significantly increased compared with members of sporadic kindreds. It was also noted that with increasing number of affected individuals in the pedigree, the risk increased: 3 affected first-degree relatives in the kindred had an SIR of 32.0 (95% CI, 10.2–74.7), 2 affected had an SIR of 6.4 (95% CI, 1.8–16.4), and 1 affected had an SIR of 4.6 (95% CI, 0.5–16.4). Compared with the general population incidence of 9 per 100,000, relatives with FPC with 3 affected individuals in the pedigree have an estimated incidence of 288 per 100,000, relatives with 2 affected individuals in the kindred have an incidence of 57.6 per 100,000, and those with 1 affected individual in the kindred have an incidence of 41.1 per 100,000.
Risk of developing pancreatic cancer in the FPC setting was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer. Unlike hereditary breast cancer or hereditary colorectal cancer syndromes, where the age of onset can be much less by 10 to 20 years compared with sporadic cases, the difference in median age at diagnosis in FPC is approximately 5 years. Compared with the general pancreatic cancer population (from SEER data) in which the mean age at diagnosis was 70.0 ± 12.1 years, the mean age among FPC cases was 65.4 ± 11.6 years. Among the PACGENE kindreds, mean ages at diagnosis did not significantly differ when stratified by number of affected individuals in the pedigree. With respect to smoking history, 37% are never smokers, 47.1% are ever smokers, and smoking status is unknown in 14.9%. In an Australian sample of 68 patients with FPC, 60.3% were never smokers. The authors and other investigators have observed increased risk of other cancers in FPC kindreds, particularly breast cancer, melanoma, and colorectal cancer. However, these risks have not been systematically disentangled from analyses that also include germline mutations in cancer susceptibility genes. In addition, much of the focus is on cancer among at-risk relatives.
Genetic studies of familial pancreatic cancer
Hereditary Syndromes with Increased Risk of Pancreatic Cancer
In 1996, Lynch and colleagues asserted that genetic factors were estimated to play a significant role in 5% of the total pancreatic cancer burden. Much research has been accomplished in the intervening time. Although novel genes that predispose to FPC remain to be discovered, increased risk of pancreatic cancer is now known to be associated with half a dozen inherited syndromes with known germline mutations, including BRCA1, BRCA2, CDKN2A, PALB2, ATM , mismatch repair genes, and PRSS1 and SPINK1 of hereditary pancreatitis. These syndromes are summarized in Table 2 , along with associated malignancies and estimates of pancreatic risk in these syndromic settings. The most prominent syndromes are hereditary breast-ovarian cancer syndrome, particularly due to germline mutations in BRCA2 , and familial atypical mole and melanoma syndrome, due to mutations in CDKN2A .
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