Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature

Mutation Research 681 (2009) 299–307

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Review

Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature Stefano Landi * Department of Biology, University of Pisa, Italy

A R T I C L E I N F O

A B S T R A C T

Article history: Received 24 June 2008 Received in revised form 9 December 2008 Accepted 18 December 2008 Available online 27 December 2008

Some cases of pancreatic cancer (PC) are described to cluster within families. With the exception of PALLD gene mutations, which explain only a very modest fraction of familial cases, the genetic basis of familial PC is still obscure. Here the literature was reviewed in order to list the known genes, environmental factors, and health conditions associated with PC or involved in the carcinogenesis of the pancreas. Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast– ovarian familial cancer), where PC is part of the cancer spectrum of the disease. In addition, in this review I ranked known/possible risk factors extending the analysis to the hereditary pancreatitis (HP), diabetes, or to specific environmental exposures such as smoking. It appears that these factors contribute strongly to only a small proportion of PC cases. Recent work has revealed new genes somatically mutated in PC, including alterations within the pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to reveal new candidate genes for the susceptibility to this disease and to better ascertain the actual contribution of the familial forms. ß 2008 Elsevier B.V. All rights reserved.

Keywords: Pancreatic cancer Genetic susceptibility Risk factors

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Known familial cancer conditions where PC is part of the spectrum . . . . . . . . . . . . . . . . . . . . 2.1. Esocrine pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.1. Familial atypical mole-multiple melanoma (FAMMM)/Melanoma-pancreatic 2.1.2. Peutz-Jeghers syndrome (PJS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.3. Familial/hereditary pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.4. Cystic fibrosis (CF) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.5. Lynch syndrome (human non-polyposis colorectal cancer). . . . . . . . . . . . . . . 2.1.6. Familial breast–ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.7. Li-Fraumeni syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1.8. Familial adenotatous polyposis (FAP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Endocrine pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.1. Multiple endocrine neoplasia (MEN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2.2. Von Hippel-Lindau syndrome (VHL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Case reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Dyskeratosis congenita. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Epidermolytic palmoplantar keratoderma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Other possible risk factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Pancreatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Smoking habit and alcohol and coffee drinking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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* Correspondence address: Dipartimento di Biologia, Universita’ di Pisa, Via Derna 1, 56126 Pisa, Italy. Tel.: +39 050 2211528; fax: +39 050 2211527. E-mail address: [email protected]. 1383-5742/$ – see front matter ß 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.mrrev.2008.12.001

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Ranking of the risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future directions and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Pancreatic cancer (PC) is a disease with a very poor prognosis, with nearly all patients dying from their disease within 7 years of surgery [1]. It is still unclear whether PC patients have predisposing genes or whether other non-genetic factors play a decisive role in the risk of this disease. A large study on twins showed the presence of inheritable factors for prostate, colorectal, and breast cancer, whereas it was unable to show inheritable factors for PC, as well as for stomach, lung, uterus, ovary, and bladder cancers [2]. However, it should be stressed that PC is typically rare, and most of these studies are statistically underpowered. Thus, the presence of inheritable genetic factors predisposing to PC cannot be ruled out on these bases. Actually, PC is known to aggregate in some families, and it has been associated with a wide variety of cancer syndromes, suggesting that genetic predisposition and/or subMendelian genetic traits are present. In 2004 the charts of all patients seen for concern of a hereditary cancer syndrome in the Cancer Genetics Clinic at the University of Alberta between 1995 and 2002 were reviewed. A total of 40 families reported a personal or family history of pancreatic cancer in the context of a possible hereditary cancer syndrome. Twentyfour (56%) of those families were suspected of having a hereditary breast and ovarian cancer syndrome. A further seven (16%) were suspected of having hereditary non-polyposis colon cancer. Another three (7%) were suspicious for hereditary pancreatitis (HP). Six (14%) of family histories were suggestive of Li-Fraumeni syndrome, von Hippel-Lindau syndrome, or a nonspecific cancer predisposition, and three (7%) were believed to be at risk for a sitespecific pancreatic cancer syndrome [3]. Moreover, when cases of PC were questioned for their familial history in a contest where no hereditary syndromes are reported, the share of site-specific cancer syndrome raised significantly. The standardized incidence rates (SIR) of PC were 4.5 (confidence interval (CI) 0.54–16.3) for one first degree relative with PC, 6.4 (CI, 1.8–16.4) for two first degree relatives and 32 (CI, 10.4–74.7) for three or more first degree relatives. This translates to an estimated incidence of pancreatic cancer of 41, 58 and 288 per 100,000, respectively, compared with the reference of 9 per 100,000 in the general US population [4]. McWilliams et al. [5] analyzed family history questionnaires from 426 patients with pancreatic cancer and compared the prevalence of malignancy reported in 3,355 of their first-degree relatives to population data from the Surveillance, Epidemiology, and End Results (SEER) Project, using age- and gender-adjusted incidence rates. They found an increased risk of pancreatic and liver carcinoma in the first-degree relatives of probands with pancreatic cancer (1.88-fold, 95% CI 1.27–2.68 and 2.7–fold, 95% CI 1.51–4.46, respectively). The risk for pancreatic cancer was nearly 3-fold when the proband was diagnosed before 60 years of age [5]. Brentnall et al. and Meckler et al. [6,7] described a striking example of autosomal dominant pancreatic cancer. The primary characteristics included early age at onset (median age 43 years) and high penetrance (more than 80%) of pancreatic cancer. Some family members developed pancreatic insufficiency before the onset of cancer. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) within a highly conserved region of the gene encoding palladin (PALLD) was found in all affected family members and was absent in non-affected members of family X. However, other authors concluded that the

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P239S mutation was specific for that family and not a common cause of familial or early-onset pancreatic cancer [8]. In the present review, I evaluated the literature in order to provide a collection of all known genes involved in the carcinogenesis of the pancreas. In addition, I ranked all the known/potential risk factors, extending the analysis to hereditary pancreatitis, diabetes, and specific environmental exposures (such as the smoking habit). 2. Known familial cancer conditions where PC is part of the spectrum 2.1. Esocrine pancreas 2.1.1. Familial atypical mole-multiple melanoma (FAMMM)/ Melanoma-pancreatic cancer syndrome FAMMM is a familial disease often associated with mutations within CDKN2A gene. Whelan et al. [9] described a kindred with an increased risk of PC, melanomas, and possibly additional types of tumors co-segregating with a CDKN2A Gly93Trp mutation. Goldstein et al. [10] also showed that PC was found within melanoma families in individuals carrying CDKN2A mutations. Studies show that all pancreatic carcinomas have inactivation of the CDKN2A gene [11]. Lynch et al. [12] stated that the Creighton University registry of familial pancreatic cancer had 159 families, of which 19 (12%) showed the FAMMM and 8 with ascertained mutations within CDKN2A. Vasen et al. [13] performed mutation analysis on 27 families with FAMMM syndrome and identified the CDKN2A-Leiden mutation in 19 families. They identified 86 patients with melanoma, and the second most frequent cancer was PC, which was observed in 15 patients from 7 families. The mean age at diagnosis of pancreatic carcinoma was 58 years, with a range from 38 to 77 years. Putative mutation carriers had an estimated cumulative risk of 17% for developing pancreatic carcinoma by age 75 years. In the 8 CDKN2A-Leiden-negative families, no cases of PC had occurred. The authors concluded that individuals with the CDKN2A-Leiden mutation show an enormous risk of developing pancreatic cancer. In another study, there was no significant association for CDKN2A mutation-negative subjects (SIR = 0.3, 95% CI 0.0–1.2), whereas mutation-positive subjects had a significantly increased risk for all cancers combined (SIR = 2.2, 95% CI 1.1–3.8) primarily because of digestive system tumors, particularly of PC, that were found 38-fold more frequently than expected (95% CI 10–97) [14]. CDKN2A encodes for p16, a 156 amino acid protein which normally blocks abnormal cell growth and proliferation by binding to complexes of cyclin-dependent kinases (CDK) 4, 6, and D. This binding inhibits the kinase activity, resulting in the arrest of the cell cycle in the G1 phase [15]. Thus, when such a pivotal regulator of the cell cycle is altered, cells show a reduced surveillance at the G1-checkpoint, increasing the possibility of accumulating mutations, and these events could lead to increased risk of PC. 2.1.2. Peutz-Jeghers syndrome (PJS) Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by melanocytic macules of the lips, buccal mucosa, and digits, multiple gastrointestinal hamartomatous polyps, and an increased risk of various neoplasms, including PC. It was often associated with mutations within STK11 gene. In a large study, Lim

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et al. [16] analyzed the incidence of cancer in 240 individuals with PJS possessing germline mutations in STK11. All pancreatic carcinomas were diagnosed between ages 34 and 49 years. The calculated risk for developing pancreatic cancer was 5% at age 40 years, increasing to 8% at age 60 years. The human STK11 gene encodes a 433 amino acid serine-threonine kinase. STK11 is known to be located both in the nucleus and the cytoplasm of all human tissues. Loss of the normal allele has been observed in polyps from patients with PJS, and loss of heterozygosity (LOH) has been noted to occur in some tumor tissues, suggesting that STK11 is a tumor suppressor gene. STK11 has been shown to cause apoptosis in intestinal epithelial cells, and is physically associated with p53, regulating specific p53-dependent apoptosis pathways. STK11 is also known to have effects on G1 cellcycle arrest, TGF-b signaling, polarity, and phosphorylating and activating the AMP-activated protein kinase (AMPK) [17]. Thus, STK11 is another key-regulator of the G1-checkpoint playing a relevant role for the carcinogenesis of the pancreas. 2.1.3. Familial/hereditary pancreatitis Pancreatitis is a continuing or relapsing inflammatory disease of the pancreas, and it is associated with a 26-fold increased risk of developing PC [18]. Familial PC is often consequence of the hereditary pancreatitis [19]. In approximately one-third of all cases, no etiologic factor can be found, and these patients are classified as having idiopathic disease. Mutations in the cationic trypsinogen gene (PRSS1) have been identified in patients with hereditary or idiopathic chronic pancreatitis. It appears that these mutations result in increased trypsin activity within the pancreatic parenchyma leading to irritation and auto-digestive stimuli within the pancreatic ducts. Most patients with idiopathic or hereditary chronic pancreatitis (including the tropical calcific pancreatitis), however, do not have mutations in PRSS1. Witt et al. [20] analyzed 96 unrelated children and adolescents for mutations in the gene encoding the Kazal-type serine protease inhibitor-1 (SPINK1), a pancreatic trypsin inhibitor. The study was prompted by the hypothesis that auto-digestion and inflammation in the pancreas may be caused by either increased proteolytic activity or decreased protease inhibition. They found mutations in 23% of the patients. In 18 patients, they detected an Asn34-to-Ser (N34S) mutation, which was homozygous in 6 patients. Idiopathic pancreatitis has been found to be associated also with mutations in the cystic fibrosis gene (CFTR), with a missense variant in the PRSS2 gene (that confers protection against chronic pancreatitis), and with variants in the chymotrypsin C gene (CTRC) [21]. Pancreatitis was shown to interact with factors such as alcohol and smoking, thus three main classes of risk were proposed: (1) low: heavy alcohol drinkers (>80 g/day); (2) moderate: heavy alcohol drinkers + carriers of the SPINK1-N34S variant or carriers of mutations within CFTR + carriers of the SPINK1-N34S variant; (3) severe: homozygotes for the SPINK1-N34S variant or carriers of mutations within PRSS1 (N291 or R122H) or smoking + any mutation within PRSS1 [21]. On a large French study, hereditary pancreatitis was shown to be a decisive risk factor for PC (SIR, standardized incidence ratio = 87, 95% CI 42–113) [22]. In this respect, other causes leading to pancreatitis, including the deficiency of lipoprotein lipase for mutations within the gene LPL, were potential risk factors for PC [23]. 2.1.4. Cystic fibrosis (CF) Because pancreas is often affected in CF, Neglia et al. [24] performed a retrospective cohort study of the occurrence of cancer in 28,511 patients with cystic fibrosis from 1985 through 1992 in the United States and Canada. The number of cases observed was compared with the number expected, calculated from populationbased data on the incidence of cancer. They also analyzed

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proportional incidence ratios to assess the association between specific cancers and cystic fibrosis in Europe. The authors found that the Odd Ratio of PC among CF patients was 31.5 (95% CI 4.8– 205). They found also an increased risk also for esophagus (OR = 14.3; 1.4–148) and bowel (OR = 9.3; 3.5–25). Interestingly, in another study (PMID: 16227367), 14 of the 166 (8.4%) young onset pancreatic cancer cases (<60 years) were carriers for CFTR mutations, compared with 217 of 5349 (4.1%) patients in the controls (p = 0.006, odds ratio 2.18, 95% confidence interval 1.24– 3.29) [25]. Because the carriers are asymptomatic and relatively frequent in the population, this should be a common risk factor that deserves deeper investigation on larger cohorts. The link between PC and CF could be explained by the fact that the histological aspect of CF associated lesions is very similar to that of ‘‘classical’’ chronic pancreatitis, and it is characterized by atrophy of acinar tissue, fibrosis, and inflammation [26]. Two reports have described an increased risk of developing chronic pancreatitis among carriers of CFTR mutations [18,27]. Thus, a pancreas suffering from inflammation as a consequence of CF status could be more prone to develop cancer, as it occurs for pancreatitis. 2.1.5. Lynch syndrome (human non-polyposis colorectal cancer) DNA replication is a faithful process, mutations occurring at a frequency of 1/109–1/1010 base pairs per cell division. Nucleotide selection at the base incorporation step and the proofreading function of DNA polymerases collectively result in an error rate of approximately 10 7 per bp per genome. The mismatch repair pathway (MMR), which is conserved from bacteria to humans, targets base substitution mismatches and insertion–deletion mismatches that arise as a result of replication errors escaping the proofreading function of DNA polymerases. Thus, MMR contributes an additional 50–1000-fold to the overall fidelity of replication [28], and its inactivation of MMR confers a strong mutator phenotype, where the rate of spontaneous mutation is greatly elevated. A hallmark of many MMR-deficient cells is instability at microsatellite regions consisting of mono- and di-nucleotide repeats. Strand slippage during replication through microsatellite regions gives rise to insertions/deletions that are normally repaired by MMR. Thus, microsatellite instability (MSI) is widely used as a diagnostic marker for loss of MMR activity in tumor cells, and it was reported also in human PC [29,30]. Defects within the MMR pathway are the basis of the so-called Lynch syndrome, also known as HNPCC, an aggressive disease manifesting colorectal cancer. PC was approximately 7 times more common than expected and about 15 times more common under the age of 60 years among carriers of mutations within MMR genes. Fourteen out of 20 cases with known age at diagnosis were under 60 years. The risk of PC seems to differ depending on which genes are affected. Unfortunately, the numbers of cases are not often adequate for an appropriate assessment of the risk. According to Geary et al. [31], carriers of MSH2 mutations showed 9 cases of PC among 64 families with 225 carriers (out of 337 individuals). The calculated familial relative risk was 2.3 (not significant), whereas the OR was 7.9 (not significant). Carriers of MLH1 mutations showed 12 cases of PC among 62 families with 244 carriers (out of 357 individuals). Thus, the calculated familial relative risk was 5.6 (P < 0.05), and the OR was 7.6 (not significant). For carriers of mutations within MSH6, a gene less frequently mutated among the MMR genes, only 1 case of PC was described among 4 families with 14 carriers (out of 29 individuals) [31]. Thus, it appears that, although of not primary relevance in families affected by HNPCC, alterations of MMR may contribute to the risk of PC. The importance of MMR for pancreatic cancer is remarked by the fact that a consistent share of PCs (almost 20%) do show

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microsatellite instability [32]; however, larger studies should be undertaken to get more robust statistics. 2.1.6. Familial breast–ovarian cancer Among 16 families with members affected associated with BRCA1 mutations, one carrier (out of 10 carriers) of the 1201-del11 bp showed pancreatic cancer at 54 years. Another family (5 carriers) showed the same mutation, but no pancreatic cancer was observed [33]. In another family with BRCA1 mutation, 2 cases of PC were described in a single large sibship, where 3 cases of breast cancer, 2 ovarian cancers, 2 leukemias, and 1 prostate cancer were also observed [34]. According to Risch et al. [35], among 60 women affected by ovarian cancer carrying a mutation in BRCA1, the risk for PC was 1.5 (95% CI 0.2–11. When the sample size was enlarged, the risk for PC in carriers of BRCA1 mutations was 3.1 (95% CI 0.45–21). In the subgroup having two relatives with cancer and the mutation within BRCA1 mutation, the relative risk was 2.3 (0.35–15) [36]. All these observations suggest that the risk of PC among BRCA1 mutation carriers is low. However, the calculation of the relative risks could be driven by the other more common forms of cancer. A contrasting case involves carriers of mutations within BRCA2. Thorlacius et al. [37] studied 21 Icelandic families and noted that in the Icelandic population, the BRCA2 999del5 mutation has been found in individuals with different tumor types including PC, and cancer of the prostate, colon, stomach, thyroid, cervix, and endometrium. Various other authors described the occurrence of PC among carriers of the BRCA2 mutations, in particular among Jews of Dutch ancestry [38,39]. According to Risch et al. [35], among 60 women affected by ovarian cancer carrying a mutation in BRCA2, the RR of ovarian, colorectal, stomach, pancreatic, or prostate cancer was 3.1 (95% CI 1.7–5.7; P = 0.0003). Risch et al. [36] found a statistically significant increased risk associated with BRCA2 mutations, particularly for ovarian cancer (RR = 7.0, 95% CI = 3.1–16), female and male breast cancer (RR = 4.6, 95% CI = 2.7–7.8, and RR = 102, 95% CI = 9.9–1050, respectively), and also PC (RR = 6.6, 95% CI = 1.9–23). When a proband had 2 relatives with cancer and the mutation within BRCA2, the calculated RR was 4.9 (95% CI 1.5–16), which increased to 10 (95% CI 2.8–38) when only the mutations within the OCC (ovarian cancer) region where considered. A similar relative risk (of 5.9) was also calculated in an independent study by Van Asperen et al. [40] on 139 Dutch BRCA2 families with 66 different pathogenic mutations ascertained nationwide. The contribution of somatic BRCA2 mutations to pancreatic cancer was also evaluated. Goggins et al. [41] screened an unselected panel of 286 pancreatic carcinomas for BRCA2 mutations and concluded that very few were somatic mutations. When BRCA2 was mutated, in almost all the cases the mutations were inherited through the germline. The finding that none of the mutation carriers identified in this study had a family history of pancreatic cancer, and just one patient had a family history of breast cancer, further supports the observation that the presence of germline BRCA2 mutations cannot be predicted by a family history of cancer. In another study performed by Goggins et al. [42], fourteen pancreatic intra-epithelial neoplasia (PaIN) were microdissected from tissues and analyzed for loss of heterozygosity at the BRCA2 locus. Loss of the wild-type allele of BRCA2 occurred in one high-grade PaIN, but in none of 13 low-grade PaINs. These findings suggest that biallelic inactivation of the BRCA2 gene is a relatively late event in pancreatic tumorigenesis. The BRCA2 gene contains 26 exons encoding a 3418-amino acid phosphoprotein, which is located predominantly in the nucleus of cells. The gene is ubiquitously expressed in a cell-cycle dependent manner, with greatest expression during the S and G2 phases of the cell cycle. BRCA2 has been implicated in regulation of gene transcription, chromatin remodeling, cell growth, DNA damage

repair, and chromosomal instability [43,44]. It has been proposed that chromosomal instability in the absence of BRCA2 may result from an accumulation of unrepaired double-strand breaks in response to an inability to re-initiate stalled replication forks (24). BRCA2-deficient cells display centrosome amplification and multipolar spindle formation during mitosis, leading to aneuploidy and significant structural alterations in chromosomes. Thus, this gene can lead to genome instability through several different mechanisms, and its deficiency can be a cause for cancer. However, the reasons why the risk is confined to a limited numbers of organs and tissues are not yet known. 2.1.7. Li-Fraumeni syndrome PC is part of the cancer spectrum of the Li-Fraumeni Syndrome, a disease occurring among carriers of mutations within TP53 gene [45]. It is has been calculated that about 1.3% of patients show PC [46]. The ability of p53 to induce cell growth arrest and apoptosis is relatively well-understood, and its importance in tumor suppression is firmly established. p53 is a major sensor of stress whose main biological activity is to activate the transcription of a variety of genes involved, among other processes, in blocking cell proliferation, and triggering apoptosis. The transcriptional activity of p53 is highly induced in response to many forms of cellular stress, including DNA damage, oncogene activation, hypoxia, and nutrient deprivation. p53 is probably the most extensively studied tumor suppressor protein with a critical role in controlling cellcycle arrest and apoptosis. The p53 protein acts as a highly regulated sequence-specific DNA binding protein that, in response to a wide variety of stress signals, undergoes post-translational stabilization and then acts as a master transcriptional regulator to induce the expression of many target genes [47,48]. Given the pivotal role of p53 in human carcinogenesis, it should not be surprising that PC is also part of the LFS spectrum. 2.1.8. Familial adenotatous polyposis (FAP) FAP, an autosomal dominant disease of the colon, is caused by mutations within the gene APC. It encodes a multi-domain protein that plays a major role in tumor suppression by antagonizing the wingless-type (Wnt) signaling transduction pathway. Specific Wnt ligands bind to their target ‘frizzled’ membrane receptor and interfere with the multi-protein destruction complex, resulting in downstream activation of gene transcription by beta-catenin. Simplistically, the multi-protein destruction complex involves Axin and APC, serving as scaffolds binding both beta-catenin and GSK3, to facilitate phosphorylation of beta-catenin by GSK-3beta. Phosphorylated beta-catenin is degraded in proteasomes by the ubiquination machinery. Unphosphorylated beta-catenin accumulates and associates with nuclear transcription factors leading to the eventual transcription and expression of target genes such as c-myc, c-jun, Fra and cyclin D1, all having cancer-activating potential. Mutations within APC activate the pathway and are the cause for FAP [49]. Among FAP carriers, there are some authors reporting cases of pancreato-blastoma, an unusual malignant neoplasm of the pediatric pancreas, that may represent an extracolonic manifestation of FAP [50]. Moreover, a study of 197 FAP pedigrees found a RR of 4.46 (95% CI 1.2–11.4) for pancreatic adenocarcinoma in patients with the syndrome [51]. The studies on this topic are limited, and larger studies are needed. The reasons why only a limited number of target tissues and organs is affected by the constitutive activation of the Wnt pathway are not yet understood. 2.2. Endocrine pancreas For the cancer of the endocrine pancreas, there are two main predisposing conditions: MEN and VHL diseases.

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2.2.1. Multiple endocrine neoplasia (MEN) MEN is an autosomal dominant disorder characterized by a high frequency of peptic ulcer disease and primary endocrine abnormalities involving the pituitary, parathyroid, and pancreas. Multiple endocrine neoplasia type I is caused by mutation in the MEN1 gene, a 10-exon gene transcribed into a 2.8 kb mRNA on 11q13. Other forms of multiple endocrine neoplasia include MEN2A and MEN2B, both of which are caused by mutations in the RET gene, and MEN4, which is caused by mutations in the CDKN1B gene [52]. Clinically the most common presentation of MEN is hyperparathyroidism, usually due to hyperplasia rather than adenoma of the parathyroid glands. The second most common manifestation is neoplasia of the pancreatic islets that eventually occurs in 80% of the patients [53]. These tumors are often multi-centric, making surgical therapy particularly difficult, and can undergo malignant transformation and metastasize. The transcription factor JunD is a direct interacting partner of menin [54], the 610 aminoacids protein encoded by MEN1. The tumor suppressor function of menin likely involves its direct binding to JunD and the inhibition of JunD-activated transcription. However, various experiments on animal models lacking MEN1 showed also the importance of menin in DNA nucleotide excision repair and in the maintenance of genome integrity [55]. 2.2.2. Von Hippel-Lindau syndrome (VHL) Von Hippel-Lindau syndrome is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar, and spinal hemangioblastoma, renal cell carcinoma, pheochromocytoma, and pancreatic tumors. Fill et al. [56] found renal cell carcinoma in 16 of 42 cases and PC in 4 of 42. Taouli et al. [57] discussed abdominal imaging findings, including pictorial images, from more than 150 patients with VHL syndrome. The most common findings were renal and pancreatic masses. A total of 633 patients with VHL were evaluated, and those with pancreatic endocrine neoplasm (PNETs) were enrolled on a prospective protocol. Overall, 108 VHL patients had PNETs (17%). The gene VHL encodes for a 213-amino acid protein expressed ubiquitously, with a tumor suppressor activity involving the inhibition of transcription elongation by its binding to elongin B and elongin C [58]. Moreover, VHL directly associates with and stabilizes p53 by suppressing MDM2-mediated ubiquitination and nuclear export of p53 [59]. Upon genotoxic stress, VHL invokes an interaction between p53 and p300 and the acetylation of p53. Moreover, VHL downregulates NF-kappa-B activity by acting as an adaptor to promote casein kinase-2-mediated inhibitory phosphorylation of CARD9, an NF-kappa-B agonist [60]. 3. Case reports

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family in which 38 persons in 4 generations had keratosis punctata. Ten of 34 affected adults developed different malignancies (PC, Hodgkin disease and renal, breast, and colonic adenocarcinomas). In 5 persons malignancies developed before the age of 50. The authors proposed that in this family mutation in the type I acidic keratin gene cluster at 17q12-q21 may be related to pathology of tumor suppressor gene(s) in the region of 17q21. 4. Other possible risk factors 4.1. Diabetes There seems to be an association between pancreas dysfunction and risk of PC, although not all studies found consistent results. The relative risk (RR) of PC comparing diabetics to non-diabetics was 2.1 (95% CI 1.6–2.8) in a prospective meta-analysis [63], and 2.6 (95% CI 1.6–4.1) in a meta-analysis of the cohort studies [63]. Ekoe et al. [64] found an Odds Ratio (OR) of 2.52 (95% CI 1.04–6.11), whereas Wideroff et al. [65] found a standardized incidence ragio (SIR) of 2.1 (95% CI 1.9-2.4) (follow up <4 years). In a recent large prospective cohort study (20,475 men and 15,183 women) in the US, the independent association between post-load plasma glucose concentration and risk of pancreatic cancer mortality among individuals without self-reported diabetes was investigated. The study showed that factors associated with abnormal glucose metabolism may play an important role in the etiology of pancreatic cancer [66]. 4.2. Pancreatitis Acute or recurrent non-familial pancreatitis is also associated with risk of PC. A large case–control study showed that a positive history of at least 7 years or more of chronic or acute pancreatitis was associated with a heightened risk of pancreatic cancer (RR = 2.04, 95% CI 1.53–2.72) [67]. A similar report from a sixcountry historical cohort of chronic pancreatitis patients indicated that the cumulative 25-year risk of pancreatic cancer with any form of chronic pancreatitis was around 4% [68]. 4.3. Nutrition Several studies pointed to some diet factors as possible risk factors for PC. Increased risks are reported for augmented intake of meat, dairy products, eggs, milk, fried food, low fresh fruit and vegetable consumption, low fibers, and particularly high risks for high consumption of salt (RR = 4.28; 95% CI 2.20–8.36), smoked meat (RR = 4.68; 95% CI 2.05–10.69), dehydrated foods (RR = 3.10; 95% CI 1.55–6.22), and fried foods (RR = 3.84; 95% CI 1.74–8.48) [69].

3.1. Dyskeratosis congenita 4.4. Smoking habit and alcohol and coffee drinking The features of dyskeratosis congenita (DKC, or DC) are cutaneous pigmentation, dystrophy of the nails, leukoplakia of the oral mucosa, continuous lacrimation due to atresia of the lacrimal ducts, often thrombocytopenia, anemia, and in most cases testicular atrophy. Only males are affected in a pattern consistent with X-linked recessive inheritance. In an extensively affected kindred, Connor and Teague [61] noted 3 previously unreported complications: Hodgkin disease, pancreatic adenocarcinoma, and deafness. This is the only case of PC reported in families with congenital diskeratosis. 3.2. Epidermolytic palmoplantar keratoderma Epidermolytic palmoplantar keratoderma can be caused by mutation in the keratin 9 gene. Stevens et al. [62] reported a large

In some multi-centre, case–control investigations, the risk of pancreatic cancer was found to rise with excessive lifetime consumption of cigarettes (RR = 2.70; 95% CI 1.95–3.74), RR = 2.5 (95% CI 1.9–3.2), or RR = 3.76 (95% CI 1.8–7.83), depending on the studies. Moreover, a positive smoking history and a first-degree relative with PC seemed to be interactive risk factors (RR = 6.02; 95% CI 1.98–18.29) (all studies reviewed in [69]). The role of alcohol in the etiology of pancreatic cancer, postulated in the mid-1960s, was supported by retrospective studies of chronic alcoholics, and by other ecologic and cohort investigations. However, the role of alcoholic beverages in the etiology of pancreas cancer is questionable because several studies have failed to establish a correlation between alcohol consumption and pancreatic cancer risk. Also for coffee drinking, the early

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304

Table 1 Risk factors for PC according to known diseases, familial factors, or environmental exposures. Classes of risk are categorized, arbitrarily, as reported in Section 5. Abbreviations used: Standardized Incidence Rate (SIR), Odd Ratio (OR), Relative Risk (RR), Confidence Interval (CI). Risk condition

Risk measure

Class of risk

Reference

Very high

PMID:10956390

Very high

PMID:15173226

Very high

PMID: 2372499

4% of patients develop PC by 40 years and 8% by 60 years

Very high

PMID: 15188174

The risk ranges between 26-fold to 60-fold, with a cumulative risk of 40% by age 70

Very high

PMID: 18184119

Familial atypical mole-multiple melanoma (FAMMM)/Melanoma-pancreatic cancer syndrome CDKN2A 17% of patients (95% CI 13–30) develop PC by the age of 75 (vs 0.53–0.85% in non-carriers). RR = 20 CDKN2A SIR = 38 (95% CI, 10–97), in patients also with melanoma SIR = 52 (95% CI, 14–133) CDKN2A 13.4-fold increase Peutz-Jeghers syndrome STK11 Hereditary pancreatitis (HP) Any of PRSS1, SPINK1, PRSS2, CTRC

PMID: 10872429 PMID: 10872414 Cystic Fibrosis CFTR, patients affected

OR = 31.5 (95% CI 4.8–205)

Very high

PMID: 7830730 PMID: 8217592

Familial pancreatic cancer (not attributable to the other ascertained cancer syndromes). For three or more first-degree relatives SIR = 32 (95% CI, 10.4–74.7)

Very high

PMID: 15059921

PALLD-dependent familial PC PALLD

Very high

PMID:11474289

Rare. Found in 1 of 84 probands with familial PC. It explains an irrelevant fraction of familial PCs.

PMID:17415588 Endocrine pancreas: Multiple Endocrine Neoplasia Any of MEN1, RET, CDKN1B

–

Limited data suggestive of very high risk

PMID: 7913018

Endocrine pancreas: Von Hippel-Lindau syndrome (VHL) VHL

17% of VHL probands show PC

Limited data suggestive of very high risk

PMID:573913

High Limited data suggestive of high risk Limited data, likely high risk

PMID:17939062 PMID: 17939062

High

PMID:17148771 PMID:16141007 PMID:15516847

High High

PMID: 15059921 PMID: 12670518

Lynch syndrome (human non-polyposis colorectal cancer; HNPCC) MLH1 Familial RR = 5.6 (p < 0.05) OR = 7.6(NS) MSH2 Familial RR = 2.3 (NS) OR = 7.9(NS) MSH6

Inconclusive

Breast/Ovarian familial cancer BRCA2

RR ranging from 5.9 to 10

Familial pancreatic cancer (not attributable to the other ascertained cancer syndromes). For two first-degree relatives SIR = 6.4 (95% CI, 1.8–16.4) when smoking + one RR = 6.02 (95% CI 1.98–18.29) first-degree relative with PC

PMID:17939062

Li-Fraumeni syndrome TP53

1.3% of all cancers in Li-Fraumeni patients are PC

Limited data suggestive of high risk

PMID: 9006316

Familial adenomatous polyposis (FAP) APC

RR ranging from 4.46 (95% CI, 1.2–11.4) to RR = 5

Intermediate

PMID:15516847 PMID: 8244108

Intermediate

PMID: 15059921

Intermediate

PMID: 8479461

Low

PMID: 7797022

Familial pancreatic cancer (not attributable to the other ascertained cancer syndromes). For one first-degree relative SIR = 4.5 (95% CI, 0.54–16.3) Non-hereditary pancreatitis

>7yrs of pancreatitis

4% cumulative lifetime risk of PC in patients with any form of pancreatitis RR = 2.04 (95% CI 1.53–2.72)

Breast/Ovarian familial cancer BRCA1

RR = 3.1 (95% CI 0.45–21)

Limited data suggestive of low risk

PMID:17148771

OR = 2.18 (1.24–3.29)

Low

PMID: 16227367

Cystic Fibrosis CFTR, carriers + young onset PC (<60 years)

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305

Table 1 (Continued ) Risk condition

Risk measure

Class of risk

Reference

RR ranges between 2.1 (95% CI 1.6–2.8) and 2.6 (95% CI 1.6–4.1)

Low

PMID: 7745774

SIR = 2.1 (95% CI 1.9–2.4)

Low

RR ranges between 2.5 (95% CI 1.9–3.2) to 2.70 (95% CI 1.95–3.74)

Low

PMID: 12670518

RR in the range between 3.10 (95% CI 1.55–6.22) for dehydrated foods, up to 4.68 (95% CI 2.05–10.69) for smoked meat

Low/Intermediate

PMID: 12670518

Case report: occurrence of one case of PC in one large pedigree

Limited data, unknown

PMID: 7272212

Case report: occurrence of PC in one large pedigree

Limited data, unknown

PMID: 8733379

Inconclusive

Likely no risk

PMID: 12670518

2.41 (95% CI 0.34–17.1)

Limited data suggestive of no risk

PMID: 15928302

Diabetes

PMID: 1287744 Very large prospective cohort study (20,475 men and 15,183 women) in the US.

Smoking habit

Diet and nutrition Excessive dietary consume of: dairy products, eggs, milk, fried food, low fresh fruit and vegetable consumption, low fibers, salted foods, smoked meat dehydrated foods and fried foods Diskeratosis congenital DKC1

Palmoplantar keratoderma Type I acidic keratin gene cluster Alcohol and coffee drinking Excluding people with chronic alcoholic pancreatitis Ataxia Telangiectasia (AT) ATM, carriers

evidence was not confirmed in more recent studies as reviewed by Ghadirian et al. [69]. 5. Ranking of the risk factors One of the aims of the review was to collect all the known and potential risk factors for PC, including defective genes, and lifestyle factors. Then, I ranked these factors in Table 1, considering broad group of risks as ‘‘very high risk,’’ ‘‘high risk,’’ ‘‘intermediate,’’ ‘‘low,’’ and ‘‘no risk.’’ Within the top category were placed those conditions conferring a risk measurable in terms of %, or with OR/ RR 10, whereas ‘‘high’’ were considered risks with RR/OR > 4.5, intermediate > 3.5, and low > 2. These classifications should be taken with caution, given the heterogeneity among studies both in the designs and in the parameter measured, and should be considered as indicative only. It is evident that most of the cited risk factors are either (a) quite common but have a low impact on personal susceptibility to the disease or (b) have a strong impact on a limited number of PC patients. 6. Future directions and conclusions In a recent publication, a comprehensive genetic analysis of 24 pancreatic cancers was carried out by Jones and co-workers [70]. They determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, and searched for deletion/amplification events. As one may expect, they found somatic mutations among several of the genes mentioned in this review, including CDKN2A, BRCA2, TP53, and also alterations within the pathways of Wnt/Notch and DNA mismatch repair. PALLD was not listed among the genes carrying somatic mutations in PC, nor was STK11, CFTR, SPINK1, PRSS1 or PRSS2, suggesting that some of the mechanisms related to pancreatitis can be important for creating a microenvironment favorable to tumor initiation, but they do not have

relevance to drive clonal expansion. Interestingly, the work depicts a landscape where many different genes are mutated at a low frequency in PC. Excluding some frequently mutated genes (TP53, CDKN1A, KRAS), PC is driven by a plethora of many other genes altered genetically and specifically for each tumor sample. When these CAN-genes were clustered according to the pathway they belong, it was clear that the different mutated genes lead to the alteration of the same pathways. In summary, what really matters is not which gene is actually mutated, but rather whether a given pathway is functioning. In different PCs, the authors found deficiencies in caspase activation (apoptosis), or in the G1/S checkpoint, the DNA damage response p53-dependent, the homofilic cell adhesion, the JNK-pathway (signal transduction), or the TGF-beta signaling (related but not limited to SMAD), to mention a few. However, it was evident that all the PCs had alterations in genes of the Wnt/Notch and Hedgehog signaling pathways. This work contributed to open new insights in understanding what are the genes modulating the individual predisposition to PC and what could be the candidate genes for the familial forms. Future studies are needed to explore whether polymorphisms within the CAN-genes evoked by Jones et al. could be associated with increased risks of PC. Moreover, familial PCs should be investigated in order to ascertain whether inherited allelic variants within CAN-genes co-segregate with the disease and play some role. This work also underlies how limited our knowledge is on the mechanisms leading to PC and how many alternate defects could drive clonal expansion. In this sense, knowledge of new CAN-genes will open new lines of research, given the fact that most of the published literature was focused on a few well-known genes. We can conclude that known causes of genetic susceptibility are an important risk factor in a small proportion of pancreatic cancer patients, particularly when associated with a strong family history of familial cancer syndromes. Future studies are warranted with

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the aim to deepen our knowledge of the role of new risk genes both for sporadic and familial PC. References [1] G. Garcea, A.R. Dennison, C.J. Pattenden, C.P. Neal, C.D. Sutton, D.P. Berry, Survival following curative resection for pancreatic ductal adenocarcinoma. A systematic review of the literature, JOP 9 (2008) 99–132. [2] P. Lichtenstein, N.V. Holm, P.K. Verkasalo, A. Iliadou, J. Kaprio, M. Koskenvuo, E. Pukkala, A. Skytthe, K. Hemminki, Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland, N. Engl. J. Med. 343 (2000) 78–85. [3] M. Lilley, D. Gilchrist, The hereditary spectrum of pancreatic cancer: the Edmonton experience, Can. J. Gastroenterol. 18 (2004) 17–21. [4] A.P. Klein, K.A. Brune, G.M. Petersen, M. Goggins, A.C. Tersmette, G.J. Offerhaus, C. Griffin, J.L. Cameron, C.J. Yeo, S. Kern, R.H. Hruban, Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds, Cancer Res. 64 (2004) 2634–2638. [5] R.R. McWilliams, K.G. Rabe, C. Olswold, A.M. de, G.M. Petersen, Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma, Cancer 104 (2005) 388–394. [6] T.A. Brentnall, M.P. Bronner, D.R. Byrd, R.C. Haggitt, M.B. Kimmey, Early diagnosis and treatment of pancreatic dysplasia in patients with a family history of pancreatic cancer, Ann. Intern. Med. 131 (1999) 247–255. [7] K.A. Meckler, T.A. Brentnall, R.C. Haggitt, D. Crispin, D.R. Byrd, M.B. Kimmey, M.P. Bronner, Familial fibrocystic pancreatic atrophy with endocrine cell hyperplasia and pancreatic carcinoma, Am. J. Surg. Pathol. 25 (2001) 1047–1053. [8] G. Zogopoulos, H. Rothenmund, A. Eppel, C. Ash, M.R. Akbari, D. Hedley, S.A. Narod, S. Gallinger, The P239S palladin variant does not account for a significant fraction of hereditary or early onset pancreas cancer, Hum. Genet. 121 (2007) 635–637. [9] A.J. Whelan, D. Bartsch, P.J. Goodfellow, Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene, N. Engl. J. Med. 333 (1995) 975–977. [10] A.M. Goldstein, M.C. Fraser, J.P. Struewing, C.J. Hussussian, K. Ranade, D.P. Zametkin, L.S. Fontaine, S.M. Organic, N.C. Dracopoli, W.H. Clark Jr., Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations, N. Engl. J. Med. 333 (1995) 970–974. [11] M. Schutte, R.H. Hruban, J. Geradts, R. Maynard, W. Hilgers, S.K. Rabindran, C.A. Moskaluk, S.A. Hahn, I. Schwarte-Waldhoff, W. Schmiegel, S.B. Baylin, S.E. Kern, J.G. Herman, Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas, Cancer Res. 57 (1997) 3126–3130. [12] H.T. Lynch, R.E. Brand, D. Hogg, C.A. Deters, R.M. Fusaro, J.F. Lynch, L. Liu, J. Knezetic, N.J. Lassam, M. Goggins, S. Kern, Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome, Cancer 94 (2002) 84–96. [13] H.F. Vasen, N.A. Gruis, R.R. Frants, D. van, V.E.T. Hille, W. Bergman, Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden), Int. J. Cancer 87 (2000) 809–811. [14] A.M. Goldstein, J.P. Struewing, M.C. Fraser, M.W. Smith, M.A. Tucker, Prospective risk of cancer in CDKN2A germline mutation carriers, J. Med. Genet. 41 (2004) 421–424. [15] W.D. Foulkes, T.Y. Flanders, P.M. Pollock, N.K. Hayward, The CDKN2A (p16) gene and human cancer, Mol. Med. 3 (1997) 5–20. [16] W. Lim, S. Olschwang, J.J. Keller, A.M. Westerman, F.H. Menko, L.A. Boardman, R.J. Scott, J. Trimbath, F.M. Giardiello, S.B. Gruber, J.J. Gille, G.J. Offerhaus, F.W. de Rooij, J.H. Wilson, A.D. Spigelman, R.K. Phillips, R.S. Houlston, Relative frequency and morphology of cancers in STK11 mutation carriers, Gastroenterology 126 (2004) 1788–1794. [17] J.H. Yoo, J.H. Yoo, Y.J. Choi, J.G. Kang, Y.K. Sun, C.S. Ki, K.A. Lee, J.R. Choi, A novel de novo mutation in the serine-threonine kinase STK11 gene in a Korean patient with Peutz-Jeghers syndrome, BMC Med. Genet. 9 (2008) 44. [18] N. Sharer, M. Schwarz, G. Malone, A. Howarth, J. Painter, M. Super, J. Braganza, Mutations of the cystic fibrosis gene in patients with chronic pancreatitis, N. Engl. J. Med. 339 (1998) 645–652. [19] M.D. Finch, N. Howes, I. Ellis, R. Mountford, R. Sutton, M. Raraty, J.P. Neoptolemos, Hereditary pancreatitis and familial pancreatic cancer, Digestion 58 (1997) 564– 569. [20] H. Witt, W. Luck, H.C. Hennies, M. Classen, A. Kage, U. Lass, O. Landt, M. Becker, Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis, Nat. Genet. 25 (2000) 213–216. [21] V. Keim, Role of genetic disorders in acute recurrent pancreatitis, World J. Gastroenterol. 14 (2008) 1011–1015. [22] V. Rebours, M.C. Boutron-Ruault, M. Schnee, C. Ferec, F. Maire, P. Hammel, P. Ruszniewski, P. Levy, Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series, Am. J. Gastroenterol. 103 (2008) 111–119. [23] T. Zhao, J. Guo, H. Li, W. Huang, X. Xian, C.J. Ross, M.R. Hayden, Z. Wen, G. Liu, Hemorheological abnormalities in lipoprotein lipase deficient mice with severe hypertriglyceridemia, Biochem. Biophys. Res. Commun. 341 (2006) 1066–1071. [24] J.P. Neglia, S.C. FitzSimmons, P. Maisonneuve, M.H. Schoni, F. Schoni-Affolter, M. Corey, A.B. Lowenfels, The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group, N. Engl. J. Med. 332 (1995) 494–499.

[25] R. McWilliams, W.E. Highsmith, K.G. Rabe, A.M. de, L.A. Tordsen, L.M. Holtegaard, G.M. Petersen, Cystic fibrosis transmembrane regulator gene carrier status is a risk factor for young onset pancreatic adenocarcinoma, Gut 54 (2005) 1661–1662. [26] N. Malats, T. Casals, M. Porta, L. Guarner, X. Estivill, F.X. Real, Cystic fibrosis transmembrane regulator (CFTR) DeltaF508 mutation and 5T allele in patients with chronic pancreatitis and exocrine pancreatic cancer. PANKRAS II Study Group, Gut 48 (2001) 70–74. [27] J.A. Cohn, K.J. Friedman, P.G. Noone, M.R. Knowles, L.M. Silverman, P.S. Jowell, Relation between mutations of the cystic fibrosis gene and idiopathic pancreatitis, N. Engl. J. Med. 339 (1998) 653–658. [28] P. Hsieh, K. Yamane, DNA mismatch repair: molecular mechanism, cancer, and ageing, Mech. Ageing Dev. 129 (2008) 391–407. [29] R. Tomaszewska, K. Okon, J. Stachura, Expression of the DNA mismatch repair proteins (hMLH1 and hMSH2) in infiltrating pancreatic cancer and its relation to some phenotypic features, Pol. J. Pathol. 54 (2003) 31–37. [30] T. Okada, S. Noji, Y. Goto, T. Iwata, T. Fujita, T. Okada, Y. Matsuzaki, M. Kuwana, M. Hirakata, A. Horii, S. Matsuno, M. Sunamura, Y. Kawakami, Immune responses to DNA mismatch repair enzymes hMSH2 and hPMS1 in patients with pancreatic cancer, dermatomyositis and polymyositis, Int. J. Cancer 116 (2005) 925–933. [31] J. Geary, P. Sasieni, R. Houlston, L. Izatt, R. Eeles, S.J. Payne, S. Fisher, S.V. Hodgson, Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC), Fam. Cancer 7 (2008) 163–172. [32] B. Nakata, Y.Q. Wang, M. Yashiro, N. Nishioka, H. Tanaka, M. Ohira, T. Ishikawa, H. Nishino, K. Hirakawa, Prognostic value of microsatellite instability in resectable pancreatic cancer, Clin. Cancer Res. 8 (2002) 2536–2540. [33] O. Johannsson, E.A. Ostermeyer, S. Hakansson, L.S. Friedman, U. Johansson, G. Sellberg, K. Brondum-Nielsen, V. Sele, H. Olsson, M.C. King, A. Borg, Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden, Am. J. Hum. Genet. 58 (1996) 441–450. [34] J. Simard, P. Tonin, F. Durocher, K. Morgan, J. Rommens, S. Gingras, C. Samson, J.F. Leblanc, C. Belanger, F. Dion, Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families, Nat. Genet. 8 (1994) 392–398. [35] H.A. Risch, J.R. McLaughlin, D.E. Cole, B. Rosen, L. Bradley, E. Kwan, E. Jack, D.J. Vesprini, G. Kuperstein, J.L. Abrahamson, I. Fan, B. Wong, S.A. Narod, Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer, Am. J. Hum. Genet. 68 (2001) 700–710. [36] H.A. Risch, J.R. McLaughlin, D.E. Cole, B. Rosen, L. Bradley, I. Fan, J. Tang, S. Li, S. Zhang, P.A. Shaw, S.A. Narod, Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada, J. Natl. Cancer Inst. 98 (2006) 1694–1706. [37] S. Thorlacius, G. Olafsdottir, L. Tryggvadottir, S. Neuhausen, J.G. Jonasson, S.V. Tavtigian, H. Tulinius, H.M. Ogmundsdottir, J.E. Eyfjord, A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes, Nat. Genet. 13 (1996) 117–119. [38] H. Ozcelik, B. Schmocker, N.N. Di, X.H. Shi, B. Langer, M. Moore, B.R. Taylor, S.A. Narod, G. Darlington, I.L. Andrulis, S. Gallinger, M. Redston, Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients, Nat. Genet. 16 (1997) 17–18. [39] E.L. Schubert, M.K. Lee, H.C. Mefford, R.H. Argonza, J.E. Morrow, J. Hull, J.L. Dann, M.C. King, BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2, Am. J. Hum. Genet. 60 (1997) 1031–1040. [40] C.J. van Asperen, R.M. Brohet, E.J. Meijers-Heijboer, N. Hoogerbrugge, S. Verhoef, H.F. Vasen, M.G. Ausems, F.H. Menko, E.B. Gomez Garcia, J.G. Klijn, F.B. Hogervorst, J.C. van Houwelingen, L.J. van’t Veer, M.A. Rookus, F.E. van Leeuwen, Cancer risks in BRCA2 families: estimates for sites other than breast and ovary, J. Med. Genet. 42 (2005) 711–719. [41] M. Goggins, M. Schutte, J. Lu, C.A. Moskaluk, C.L. Weinstein, G.M. Petersen, C.J. Yeo, C.E. Jackson, H.T. Lynch, R.H. Hruban, S.E. Kern, Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas, Cancer Res. 56 (1996) 5360–5364. [42] M. Goggins, R.H. Hruban, S.E. Kern, BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications, Am. J. Pathol. 156 (2000) 1767–1771. [43] S.V. Tavtigian, J. Simard, J. Rommens, F. Couch, D. Shattuck-Eidens, S. Neuhausen, S. Merajver, S. Thorlacius, K. Offit, D. Stoppa-Lyonnet, C. Belanger, R. Bell, S. Berry, R. Bogden, Q. Chen, T. Davis, M. Dumont, C. Frye, T. Hattier, S. Jammulapati, T. Janecki, P. Jiang, R. Kehrer, J.F. Leblanc, J.T. Mitchell, J. rthur-Morrison, K. Nguyen, Y. Peng, C. Samson, M. Schroeder, S.C. Snyder, L. Steele, M. Stringfellow, C. Stroup, B. Swedlund, J. Swense, D. Teng, A. Thomas, T. Tran, M. Tranchant, J. Weaver-Feldhaus, A.K. Wong, H. Shizuya, J.E. Eyfjord, L. Cannon-Albright, M. Tranchant, F. Labrie, M.H. Skolnick, B. Weber, A. Kamb, D.E. Goldgar, The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds, Nat. Genet. 12 (1996) 333–337. [44] A.R. Venkitaraman, Cancer susceptibility and the functions of BRCA1 and BRCA2, Cell 108 (2002) 171–182. [45] J.M. Varley, Germline TP53 mutations and Li-Fraumeni syndrome, Hum. Mutat. 21 (2003) 313–320. [46] P. Kleihues, B. Schauble, H.A. zur, J. Esteve, H. Ohgaki, Tumors associated with p53 germline mutations: a synopsis of 91 families, Am. J. Pathol. 150 (1997) 1–13. [47] B. Vogelstein, D. Lane, A.J. Levine, Surfing the p53 network, Nature 408 (2000) 307–310. [48] K.H. Vousden, D.P. Lane, p53 in health and disease, Nat. Rev. Mol. Cell Biol. 8 (2007) 275–283. [49] R. Karim, G. Tse, T. Putti, R. Scolyer, S. Lee, The significance of the Wnt pathway in the pathology of human cancers, Pathology 36 (2004) 120–128.

S. Landi / Mutation Research 681 (2009) 299–307 [50] S.C. Abraham, T.T. Wu, D.S. Klimstra, L.S. Finn, J.H. Lee, C.J. Yeo, J.L. Cameron, R.H. Hruban, Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas: frequent alterations in the APC/beta-catenin pathway and chromosome 11p, Am. J. Pathol. 159 (2001) 1619– 1627. [51] F.M. Giardiello, G.J. Offerhaus, D.H. Lee, A.J. Krush, A.C. Tersmette, S.V. Booker, N.C. Kelley, S.R. Hamilton, Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis, Gut 34 (1993) 1394–1396. [52] R.V. Thakker, Multiple endocrine neoplasia—syndromes of the twentieth century, J. Clin. Endocrinol. Metab. 83 (1998) 2617–2620. [53] B. Skogseid, J. Rastad, K. Oberg, Multiple endocrine neoplasia type 1. Clinical features and screening, Endocrinol. Metab. Clin. North Am. 23 (1994) 1–18. [54] S.K. Agarwal, S.C. Guru, C. Heppner, M.R. Erdos, R.M. Collins, S.Y. Park, S. Saggar, S.C. Chandrasekharappa, F.S. Collins, A.M. Spiegel, S.J. Marx, A.L. Burns, Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription, Cell 96 (1999) 143–152. [55] V. Busygina, K. Suphapeetiporn, L.R. Marek, R.S. Stowers, T. Xu, A.E. Bale, Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1, Hum. Mol. Genet. 13 (2004) 2399–2408. [56] W.L. Fill, J.M. Lamiell, N.O. Polk, The radiographic manifestations of von HippelLindau disease, Radiology 133 (1979) 289–295. [57] B. Taouli, M. Ghouadni, J.M. Correas, P. Hammel, A. Couvelard, S. Richard, V. Vilgrain, Spectrum of abdominal imaging findings in von Hippel-Lindau disease, AJR Am. J. Roentgenol. 181 (2003) 1049–1054. [58] D.R. Duan, A. Pause, W.H. Burgess, T. Aso, D.Y. Chen, K.P. Garrett, R.C. Conaway, J.W. Conaway, W.M. Linehan, R.D. Klausner, Inhibition of transcription elongation by the VHL tumor suppressor protein, Science 269 (1995) 1402–1406. [59] J.S. Roe, H. Kim, S.M. Lee, S.T. Kim, E.J. Cho, H.D. Youn, p53 stabilization and transactivation by a von Hippel-Lindau protein, Mol. Cell 22 (2006) 395–405. [60] H. Yang, Y.A. Minamishima, Q. Yan, S. Schlisio, B.L. Ebert, X. Zhang, L. Zhang, W.Y. Kim, A.F. Olumi, W.G. Kaelin Jr., pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappaB agonist Card9 by CK2, Mol. Cell 28 (2007) 15–27.

307

[61] J.M. Connor, R.H. Teague, Dyskeratosis congenita. Report of a large kindred, Br. J. Dermatol. 105 (1981) 321–325. [62] H.P. Stevens, D.P. Kelsell, I.M. Leigh, L.S. Ostlere, K.D. MacDermot, M.H. Rustin, Punctate palmoplantar keratoderma and malignancy in a four-generation family, Br. J. Dermatol. 134 (1996) 720–726. [63] J. Everhart, D. Wright, Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis, JAMA 273 (1995) 1605–1609. [64] J.M. Ekoe, P. Ghadirian, A. Simard, J. Baillargeon, C. Perret, Diabetes mellitus and pancreatic cancer: a case–control study in greater Montreal, Quebec, Canada, Rev. Epidemiol. Sante Publique 40 (1992) 447–453. [65] L. Wideroff, G. Gridley, L. Mellemkjaer, W.H. Chow, M. Linet, S. Keehn, K. BorchJohnsen, J.H. Olsen, Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark, J. Natl. Cancer Inst. 89 (1997) 1360–1365. [66] S.M. Gapstur, P.H. Gann, W. Lowe, K. Liu, L. Colangelo, A. Dyer, Abnormal glucose metabolism and pancreatic cancer mortality, JAMA 283 (2000) 2552–2558. [67] P. Bansal, A. Sonnenberg, Pancreatitis is a risk factor for pancreatic cancer, Gastroenterology 109 (1995) 247–251. [68] A.B. Lowenfels, P. Maisonneuve, G. Cavallini, R.W. Ammann, P.G. Lankisch, J.R. Andersen, E.P. Dimagno, A. ndren-Sandberg, L. Domellof, Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group, N. Engl. J. Med. 328 (1993) 1433–1437. [69] P. Ghadirian, H.T. Lynch, D. Krewski, Epidemiology of pancreatic cancer: an overview, Cancer Detect. Prev. 27 (2003) 87–93. [70] S. Jones, X. Zhang, D.W. Parsons, J.C. Lin, R.J. Leary, P. Angenendt, P. Mankoo, H. Carter, H. Kamiyama, A. Jimeno, S.M. Hong, B. Fu, M.T. Lin, E.S. Calhoun, M. Kamiyama, K. Walter, T. Nikolskaya, Y. Nikolsky, J. Hartigan, D.R. Smith, M. Hidalgo, S.D. Leach, A.P. Klein, E.M. Jaffee, M. Goggins, A. Maitra, C. IacobuzioDonahue, J.R. Eshleman, S.E. Kern, R.H. Hruban, R. Karchin, N. Papadopoulos, G. Parmigiani, B. Vogelstein, V.E. Velculescu, K.W. Kinzler, Core signaling pathways in human pancreatic cancers revealed by global genomic analyses, Science 321 (2008) 1801–1806.