Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with not fully understood etiology. Interleukin 1β (IL1β) plays an important role in pancreatic pathology, especially carcinogenesis, but its role in pNET development remains unknown. The aim of this study was to analyze the association between IL1β polymorphisms and susceptibility to pNETs. IL1β −511 C/T and +3954 C/T single-nucleotide polymorphisms (SNPs) were analyzed by real-time polymerase chain reaction–SNP analysis. IL1β serum values in pNET patients were also determined. Association between high-expression C/T −511 IL1β genotype and susceptibility to pNET (p=0.042) was found, especially with functional pNET (p=0.014), where it was associated with the T allele (p=0.016). Combination of genotype analyses confirmed carriers of −511/+3954 CTCT to be at risk of developing functional pNETs (p=0.006) and carriers of −511/+3954 CTCC at risk of developing nonfunctional pNETs (p=0.019). IL1β serum levels of all patients were below the limit of detection. Our results suggest IL1β involvement in pNET development, and we also found association between the IL1β −511 SNP and susceptibility to pNET, especially functional pNETs. Nonfunctional pNETs seem to have inferior prognosis when compared with functional pNETs. It is possible that they differ in tumor microenvironment and that nonfunctional tumors share similarities with adenocarcinoma. We believe that our findings will contribute to understanding of the etiology and possible novel prognostic markers for pNETs when future studies investigating the serum and tumor tissue IL1β levels are done.
Introduction
Pancreatic neuroendocrine tumors (pNETs) are uncommon, mostly well-differentiated and indolent neuroendocrine neoplasms. They are largely nonfunctional, but when associated with hormone oversecretion they can cause hypoglycemia (insulinoma), Zollinger-Ellison syndrome (gastrinoma), Verner-Morrison (VIP-oma), and carcinoid syndrome (Massironi et al., 2008). Molecular mechanisms of pNET genesis are poorly understood but have been the focus of many recent reports (Chan et al., 2003; House et al., 2003; Franko et al., 2010). Chronic inflammation has been suggested as a contributor in development of pancreatic diseases such as diabetes and pancreatic cancer. Interleukin 1β (IL1β), a key proinflammatory cytokine encoded by the IL1β gene, has been associated with chronic inflammation and plays an important role in pancreatic inflammatory diseases, including pancreatic cancer (Chen et al., 2001). Elevated levels of IL1β protein enhances the intensity of the inflammatory response, damages pancreatic beta cells through nitric oxide production leading to their apoptosis, and has also been found to inhibit insulin release in pancreatic islets cultured in vitro or in insulinoma cells (Corbett et al., 1993; Ankarcrona et al., 1994). IL1β levels are regulated at the transcriptional level, and polymorphisms in the IL1β gene have been found not only to influence levels of IL1β but also to change susceptibility to different diseases (Pociot et al., 1992; Chen et al., 2006). The IL1β gene is located in the IL1 cluster on chromosome 2q. A single-nucleotide polymorphism (SNP) in the proximal promoter region of the IL1β gene, −511C/T, is associated with gastrointestinal cancers such as gastric (El-Omar et al., 2000), hepatocellular (Wang et al., 2003), and pancreatic carcinoma (Barber et al., 2000). SNP +3954 in exon 5 of the IL1β gene was also recently demonstrated to influence survival of patients with unresectable pancreatic cancer (Barber et al., 2000; Hamacher et al., 2009). Functionally, IL1β was shown to mediate adhesion and invasion of pancreatic cancer cells, and through autocrine and paracrine production it contributes to chemoresistance of pancreatic cancer cells (Ebrahimi et al., 2004; Muerkoster et al., 2004; Greco et al., 2005; ten Kate et al., 2006). The roles of IL1β −511C/T and +3954 C/T genotypes in the development of pNETs remain unknown. pNETs represent a heterogeneous group with varying tumor biology and prognosis; they can either occur as solitary tumors, and up to 15% of pNETS are a part of inherited syndromes. The aim of this study was to investigate the association between IL1β −511 C/T and +3954 C/T polymorphisms and susceptibility to functional and nonfunctional pNETs. The secondary aim was to investigate the serum values of IL1β protein in pNET patients.
Patients and Methods
Patients
The study included 60 consecutive patients diagnosed with pNETs and 60 healthy unrelated individuals as controls. Patients as well as controls were Caucasian and of Croatian nationality. They were recruited from the Department of Endocrinology, Diabetes, and Metabolism, University Hospital “Sestre milosrdnice” and all gave written informed consent for the participation in this study. Among patients, 37 had nonfunctional and 23 functional tumors, associated with hypoglycemia (13) (Barber et al., 2000), Verner-Morrison (1) (Massironi et al., 2008), carcinoid (6) (Ankarcrona et al., 1994), and Zollinger-Ellison (3) (House et al., 2003) syndromes, respectively. pNETs were diagnosed by standard procedures (first imaging-endoscopic ultrasound [EUS], computed tomography, and when possible, octreoscan). Diagnosis was confirmed by either immunocytochemistry following fine needle aspiration (FNA) or patohistological analysis after surgical removal. The study was approved by the Ethics Committees of the University Hospital “Sestre Milosrdnice” and School of Medicine University of Zagreb. DNAs from 60 healthy volunteers were obtained from the Croatian Tumor and DNA Bank for Basic Research (Spaventi et al., 1994).
Methods
DNA isolation
Genomic DNAs were isolated from peripheral ethylenediaminetetraacetic acid-treated blood of patients and healthy controls using proteinase K digestion and phenol–chloroform extraction.
SNP genotyping
Real-time polymerase chain reaction (PCR)–SNP analysis of IL1β −511C/T (rs16944) and +3954C/T (rs1143634) was performed using an ABI PRISM 7000 SDS (Applied Biosystems) and predeveloped TaqMan SNP genotyping assays C_1839943_10 (−511CT) and C_9546517_10 (+3954CT) (Applied Biosystems). PCR was carried out according to the manufacturer's protocol. For quality control, 15% of randomly selected samples of both cases and control were analyzed a second time, without finding any discrepancies. Control samples covering three possible SNP genotypes and no template control were run in parallel with tested samples in each experiment.
IL1β serum levels
Serum IL1β levels were determined for all patients by double-sided chemiluminescent immunometric method using IL1β monoclonal antibody with the IMMULITE system. Lower limit of detectability for the IL1β serum levels was 5 pg/mL (Diagnostic Products Corporation, Corporate offices), and there was no possibility to measure values lower than that mentioned. All patients had serum levels below the lower limit of detection. Results were not influenced by serum bilirubin or lipid levels or by hemoglobin concentration in case of hemolytic sera. Serum samples were stored at −20°C for up to 6 months prior to analysis.
Statistics
This study was planned as a study of independent cases and controls with one control per case, and the power test was calculated. Prior data indicate that the probability of exposure among controls is 0.5. If the true odds ratio (OR) for disease in exposed subjects relative to unexposed subjects is 3, we will need to study 58 case patients and 58 control patients to be able to reject the null hypothesis that this OR equals 1 with probability (power) 0.8. The type I error probability associated with this test of this null hypothesis is 0.05. We used an uncorrected chi-squared statistic to evaluate the null hypothesis.
The distribution of IL1β −511C/T and +3954 C/T polymorphisms was compared between pNET patients and controls. For the mentioned analyses, OR was used. For the analysis of distribution of genotypes and alleles between the patients with functional and nonfunctional pNETs, χ2 and Fisher's test were used when appropriate. The OR and 95% confidence interval (CI) with Haldan's correction was performed for the analysis of −511/+3954 genotype/haplotype differences between patients with functional and nonfunctional pNETs and healthy controls. The level of significance was 0.05. Genotype frequencies were distributed in accordance with the Hardy–Weinberg equilibrium.
Results
The present study included 60 consecutive patients diagnosed with pNETs by standard diagnostic procedures and 60 controls. Patients' as well as controls' characteristics are given in Table 1.
Table 1.
Characteristics of Pancreatic Neuroendocrine Tumor Patients
| Pancreatic neuroendocrine tumor cases | Healthy controls | |
|---|---|---|
| Number (n) | 60 | 60 |
| Mean age, years (range) | 55.12 (22–85) | 50.33 (26–75) |
| Gender (n) | Male: 24 | 31 |
| Female: 36 | 29 | |
| Tumor functional status (n) | Functional: 23 | |
| Nonfunctional: 37 |
DNAs were genotyped using real-time PCR-SNP method and allelic discrimination analysis (Fig. 1). IL1β −511 C/T and +3954 C/T distribution differences between patients with pNETs and healthy controls are given in Table 2. There was a statistically significant association between the high-expression C/T genotype and risk of pNET development (OR, 2.217; 95% CI, 1.022−4.812; p=0.042; Table 2), and combined C/T and T/T high-expression genotypes had a tendency for statistical significance (OR, 2.000; 95% CI, 0.956−4.182; p=0.063). The statistical significance was especially associated with functional pNETs where high-expression IL1β −511 C/T (OR, 3.913; 95% CI, 1.241−12.342; p=0.014; Table 3) and high-expression C/T and T/T −511 IL1β genotypes were associated with the risk of functional pNET development (OR, 3.600; 95% CI, 1.183−10.952; p=0.016; Table 3). Among patients with functional pNETs, we observed the tendency of the more frequent T allele (OR, 1.8843; 95% CI, 0.9379−3.7856; p=0.0762; Table 3). On the other hand, the +3954 C/T genotype was similarly distributed between functional pNET patients and healthy controls (Table 3).
FIG. 1.
Real-time polymerase chain reaction–single-nucleotide polymorphism allelic discrimination analysis of IL1β −511 C/T polymorphism.
Table 2.
Genotype Frequencies of IL1β −511 C/T and +3954 C/T Polymorphisms in Pancreatic Neuroendocrine Tumor Patients and Healthy Controls
| SNP genotype | Controls n=60 (%) | Patients n=60 (%) | OR (95% CI) | p-Value | |
|---|---|---|---|---|---|
| IL1β −511C/T | C/C | 30 (50) | 20 (33.3) | 1 | |
| C/T | 23 (38.3) | 34 (56.7) | 2.217 (1.022–4.812) | 0.042 | |
| T/T | 7 (11.7) | 6 (10) | 1.286 (0.376–4.392) | 0.689 | |
| C/T+T/T | 30 (50) | 40 (66.7) | 2.000 (0.956–4.182) | 0.063 | |
| C | 83 (69.2) | 74 (61.7) | 1 | ||
| T | 37 (30.8) | 46 (38.3) | 1.394 (0.817–2.379) | 0.222 | |
| IL1β +3954C/T | C/C | 32 (53.3) | 28 (46.7) | 1 | |
| C/T | 25 (41.7) | 31 (51.6) | 1.417 (0.682–2.945) | 0.349 | |
| T/T | 3 (5) | 1 (1.7) | 0.381 (0.038–3.874) | 0.387 | |
| C/T+T/T | 28 (46.7) | 32 (53.3) | 1.306 (0.638–2.676) | 0.465 | |
| C | 89 (74.2) | 87 (72.5) | 1 | ||
| T | 31 (25.8) | 33 (27.5) | 1.089 (0.614–1.930) | 0.770 | |
SNP, single-nucleotide polymorphism; OR, odds ratio; CI, confidence interval.
Table 3.
Genotype Frequencies of IL1β −511 C/T and +3954 C/T Polymorphisms in Functional Pancreatic Neuroendocrine Tumor Patients and Healthy Controls
| SNP genotype | Controls n=60 (%) | FPpatients n=23 (%) | OR (95% CI) | p-Value | |
|---|---|---|---|---|---|
| IL1β −511C/T | C/C | 30 (50) | 5 (21.7) | 1 | |
| C/T | 23 (38.3) | 15 (65.2) | 3.913 (1.241–12.342) | 0.014 | |
| T/T | 7 (11.7) | 3 (13.1) | 2.571 (0.493–13.402) | 0.274 | |
| C/T+T/T | 30 (50) | 18 (78.3) | 3.600 (1.183–10.952) | 0.016 | |
| C | 83 (69.2) | 25 (54.3) | 1 | ||
| T | 37 (30.8) | 21 (45.7) | 1.884 (0.938–3.786) | 0.076 | |
| IL1β +3954C/T | C/C | 32 (53.3) | 8 (34.8) | 1 | |
| C/T | 25 (41.7) | 15 (65.2) | 2.400 (0.879–6.557) | 0.082 | |
| T/T | 3 (5) | 0 (0) | 0.546 (0.026–11.626)a | 0.679a | |
| C/T+T/T | 28 (46.7) | 15 (65.2) | 2.143 (0.791–5.806) | 0.128 | |
| C | 89 (74.2) | 31 (67.4) | 1 | ||
| T | 31 (25.8) | 15 (32.6) | 1.389 (0.663–2.911) | 0.387 | |
With Haldan correction.
FP, functional pancreatic neuroendocrine tumor.
Table 4 presents distribution differences in −511 C/T and +3954 C/T genotypes between patients with nonfunctional pNETs and healthy controls. There were no statistically significant associations between the analyzed IL1β SNPs and risk of developing nonfunctional pNETs. In Table 5, IL1β −511 C/T and +3954 C/T distribution differences between patients with functional and nonfunctional pNETs are given. There were no statistically significant differences between the patients with functional and nonfunctional pNETs with respect to IL1β −511 C/T and +3954 C/T genotypes.
Table 4.
Genotype Frequencies of IL1β −511 C/T and Polymorphisms in Nonfunctional Pancreatic Neuroendocrine Tumor Patients and Healthy Controls
| SNP genotype | Controls n=60 (%) | NFPpatients n=37 (%) | OR (95% CI) | p-Value | |
|---|---|---|---|---|---|
| IL1β −511C/T | C/C | 30 (50) | 15 (40.5) | 1 | |
| C/T | 23 (38.3) | 19 (51.4) | 1.652 (0.694–3.936) | 0.255 | |
| T/T | 7 (11.7) | 3 (8.1) | 0.857 (0.194–3.795) | 0.838 | |
| C/T+T/T | 30 (50) | 22 (59.5) | 1.467 (0.640–3.359) | 0.363 | |
| C | 83 (69.2) | 49 (66.2) | 1 | ||
| T | 37 (30.8) | 25 (33.8) | 1.145 (0.617–2.124) | 0.669 | |
| IL1β +3954C/T | C/C | 32 (53.3) | 20 (54.1) | 1 | |
| C/T | 25 (41.7) | 16 (43.2) | 1.024 (0.442–2.372) | 0.956 | |
| T/T | 3 (5) | 1 (2.7) | 0.533 (0.052–5.488) | 0.582 | |
| C/T+T/T | 28 (46.7) | 17 (45.9) | 0.971 (0.427–2.209) | 0.945 | |
| C | 89 (74.2) | 56 (75.7) | 1 | ||
| T | 31 (25.8) | 18 (24.3) | 0.923 (0.472–1.804) | 0.814 | |
NFP, non-functional pancreatic neuroendocrine tumor.
Table 5.
Genotype Frequencies of IL1β −511 C/T and +3954 C/T Polymorphisms in Patients with Functional and Nonfunctional Pancreatic Neuroendocrine Tumors
| Polymorphism | NFP n=37 (%) | FP n=23 (%) | p-Value | |
|---|---|---|---|---|
| IL1β −511 | C/C | 15 (40.5) | 5 (21.7) | 0.334 |
| C/T | 19 (51.4) | 15 (65.2) | ||
| T/T | 3 (8.1) | 3 (13.1) | ||
| C/T+T/T | 22 (59.5) | 18 (78.3) | 0.133 | |
| C | 49 (66.2) | 25 (54.3) | 0.194 | |
| T | 25 (33.8) | 21 (45.7) | ||
| IL1β +3954 | C/C | 20 (54.1) | 8 (34.8) | 0.220 |
| C/T | 16 (43.2) | 15 (65.2) | ||
| T/T | 1 (2.7) | 0 (0) | ||
| C/T+T/T | 17 (45.9) | 15 (65.2) | 0.146 | |
| C | 56 (75.7) | 31 (67.4) | 0.323 | |
| T | 18 (24.3) | 15 (32.6) | ||
Tables 6 and 7 show at risk population for developing functional and nonfunctional pNETs according to −511/+3954 genotype combinations. There was a statistically significant association between CTCT −511/+3954 genotype combination and risk of functional pNET development (OR, 8.556; 95% CI, 1.526−47.958; p=0.006; Table 6), whereas patients with the CTCC −511/+3954 genotype combination were associated with risk of nonfunctional pNET development (OR, 5.026; 95% CI, 1.169−21.590; p=0.019; Table 7). Serum IL1β levels analyzed for all patients were lower than 5 pg/mL (threshold set by manufacturer), with no possibility to approximate the IL1β levels.
Table 6.
Combinations of IL1β −511 and +3954 Genotypes in Functional Pancreatic Neuroendocrine Tumor Patients and Healthy Controls
| IL1β genotypes/haplotypes−511, +3954 | Controls n=60 (%) | FP patients n=23 (%) | OR (95% CI) | p-Value |
|---|---|---|---|---|
| CC CC | 14 (23.3) | 2 (8.7) | 1 | |
| CC CT | 15 (25) | 3 (13.0) | 1.400 (0.203–9.663) | 0.731 |
| CC TT | 1 (1.7) | 0 (0) | 1.933 (0.060–62.175) | 0.721a |
| CT CC | 13 (21.7) | 4 (17.4) | 2.154 (0.336–13.804) | 0.407 |
| CT CT | 9 (15) | 11 (47.8) | 8.556 (1.526–47.958) | 0.006 |
| CT TT | 1 (1.7) | 0 (0) | 1.933 (0.060–62.175) | 0.721a |
| TT CC | 5 (8.3) | 2 (8.7) | 2.800 (0.307–25.525) | 0.365 |
| TT CT | 1 (1.7) | 1 (4.3) | 7.000 (0.302–162.212) | 0.238 |
| TT TT | 1 (1.7) | 0 (0) | 1.933 (0.060–62.175) | 0.721a |
With Haldan correction.
Table 7.
Combinations of IL1β −511 and +3954 Genotypes in Nonfunctional Pancreatic Neuroendocrine Tumor Patients and Healthy Controls
| IL1β genotypes/haplotypes−511, +3954 | Controls n=60 (%) | NFP patients n=37(%) | OR (95% CI) | p-Value |
|---|---|---|---|---|
| CC CC | 14 (23.3) | 3 (8.1) | 1 | |
| CC CT | 15 (25) | 11 (29.7) | 3.422 (0.787–14.881) | 0.083 |
| CC TT | 1 (1.7) | 1 (2.7) | 4.667 (0.223–97.502) | 0.332 |
| CT CC | 13 (21.7) | 14 (37.8) | 5.026 (1.169–21.590) | 0.019 |
| CT CT | 9 (15) | 5 (13.5) | 2.593 (0.494–13.613) | 0.252 |
| CT TT | 1 (1.7) | 0 (0) | 1.381 (0.046–41.665) | 0.856a |
| TT CC | 5 (8.3) | 3 (8.1) | 2.800 (0.420–18.690) | 0.289 |
| TT CT | 1 (1.7) | 0 (0) | 1.381 (0.046–41.665) | 0.856a |
| TT TT | 1 (1.7) | 0 (0) | 1.381 (0.046–41.665) | 0.856a |
With Haldan correction.
Discussion
pNETs are uncommon neoplasms with an incidence of <1 per 100,000 person-years in population-based studies. They are usually more indolent than pancreatic adenocarcinoma and have a better prognosis. The origin of these tumors is not fully known, but proinflammatory cytokines were found in pNET tissue (Massironi et al., 2008; Chan et al., 2003; Franko et al., 2010). IL1β acts as autocrine and paracrine stimuli in carcinogenesis of different tumor types (El-Omar et al., 2000). In this study we examined the association between the IL1β gene SNPs with neuroendocrine pancreatic tumors in Croatian population. The main drawback of this study is the small sample size of pNET patients, but according to power test, the present result is enough to give an appropriate answer for the role of IL1β −511C/T and +3954 C/T in pNET susceptibility.
Our results showed statistically significant association between the IL1β −511C/T genotype and functional pNET risk. We observed a significantly increased prevalence of the −511C/T genotype in functional pNET cases with an OR of 3.913. Similar to our results, the −511C/T genotype contributed to an increased risk for pancreatic carcinoma, with an OR of 1.42, and also NSCLC and gastric cancer, with an OR of 1.9 and 1.8, respectively (El-Omar et al., 2000; Zienolddiny et al., 2004).
Recently, it was found that an exon 5 SNP (+3954) of the IL1β gene predisposes to pancreatic cancer. Homozygosity for the minor IL1β +3954 T allele correlates with increased IL1β secretion and shortens survival of patients with advanced pancreatic cancer (Barber et al., 2000). We observed a higher prevalence of the +3954 C/T genotype in patients with functional pNETs (65.2% vs. 43.2%) than in nonfunctional pNETs, but the difference did not reach statistical significance (p=0.220). IL1β is a pleiotropic cytokine acting at multiple levels during carcinogenesis. It participates in hormone secretion; in the setting of pancreas it influences susceptibility to tumor development, tumor invasiveness, metastasis, and angiogenesis (Corbett et al., 1993; Apte et al., 2006).
Studies investigating IL1β serum levels in patients with different solid tumors suggest that IL1β is a product of tumor cells, and as such can be used as a prognostic marker (Yoshida et al., 2002). According to Deans et al. (2006), IL1β serum levels in gastroesophageal carcinoma correlate with systemic inflammation and are a marker of worse prognosis, whereas in colorectal carcinogenesis, IL1β positively correlated with carcinoembrional antigen (CEA), a marker of tumor exocrine differentiation leading also to a worse prognosis (Abdul and Hoosein, 2002). In our patient population, serum IL1β levels were below the limit of detectability (5 pg/mL). In other available research, serum levels of IL1β in different epithelial tumors were usually around 1 pg/mL, and in healthy subjects the IL1β levels were lower than 0.2 pg/mL (Yoshida et al., 2002). This leaves the possibility that other, more sensitive laboratory methods would be needed to determine precise IL1β levels, which would give insight into their value as an additional tumor marker. In vitro studies of pancreatic cell lines have detected accumulation of IL1β −511C/T in locally advanced, undifferentiated, and metastatic pancreatic cancers. Further, the probability of pancreatic cancer resectability was significantly lower in the IL1β high-expression genotype −511C/T (Hamacher et al., 2009). Additionally, new insight into the role of IL1β in pNET tumorigenesis would be obtained through cell culture research as well as immunohistochemistry studies of pNET tissues.
Our results showed statistically significant association between the IL1β −511C/T genotype and CTCT −511/+3954 genotype combination and susceptibility to functional pNET development and patients with CTCC −511/+3954 genotype combination were associated with risk to nonfunctional pNET development. All these results suggest IL1β involvement in pNET development.
Acknowledgments
This study was supported by grants (098-0982464-2508 and 134-1342428-0491) from the Ministry of Science, Education, and Sports of the Republic of Croatia.
Disclosure Statement
The authors confirm that no conflict of interest exists in this study.
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