P- Reviewer: Guo XZ, Ooi LLPJ S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ
Published online Jun 15, 2016. doi: 10.4251/wjgo.v8.i6.520
Peer-review started: February 14, 2016
First decision: March 1, 2016
Revised: March 1, 2016
Accepted: March 17, 2016
Article in press: March 17, 2016
Published online: June 15, 2016
AIM: To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development.
METHODS: A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls).
RESULTS: The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients.
CONCLUSION: The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only.
Core tip: Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of rare neoplasms derived from pancreatic endocrine cells and have significantly different tumor biology and present better prognosis compared with tumors of the exocrine pancreas, like pancreatic adenocarcinomas. It is widely accepted that chronic inflammation contributes to pathogenesis of many pancreatic diseases, including pancreatic carcinogenesis. Interleukin 1β (IL-1β) is a highly active pro-inflammatory cytokine with multiple biological effects, such as directing cancer cells to either neuroendocrine differentiation or to development of adenocarcinoma. The purpose of the study was to evaluate the association between the IL-1β polymorphisms and the pNET development.
- Citation: Karakaxas D, Sioziou A, Aravantinos G, Coker A, Papanikolaou IS, Liakakos T, Dervenis C, Gazouli M. Genetic polymorphisms of interleukin 1β gene and sporadic pancreatic neuroendocrine tumors susceptibility. World J Gastrointest Oncol 2016; 8(6): 520-525
- URL: https://www.wjgnet.com/1948-5204/full/v8/i6/520.htm
- DOI: https://dx.doi.org/10.4251/wjgo.v8.i6.520
Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of rare neoplasms derived from pancreatic endocrine cells[1-5]. The annual incidence of pNETs is estimated to be approximately 3.65 per 100000 individuals in the United States and occur sporadically or may be associated with genetic syndromes such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome (VHL), von Recklinghausen disease (neurofibromatosis NF-1), and tuberous sclerosis complex (TSC)[6-8].
PNETs are mainly considered functionally inactive tumors, but when related with hormone or peptide overproduction, such as insulin, gastrin, glucagon, vasoactive intestinal polypeptide (VIP) and somatostatin they are responsible for many characteristic clinical syndromes, with insulinoma being the most common PNETs are usually asymptomatic[9,10], have significantly different tumor biology, and present better prognosis compared with tumors of the exocrine pancreas, like pancreatic adenocarcinomas (PDACs).
The molecular basis of pNETs pathogenesis is poorly characterized but several recent reports have been conducted in order to clarify their etiology.
It is widely accepted that chronic inflammation contributes to pathogenesis of many pancreatic diseases, including pancreatic carcinogenesis[13,14]. However, the exact mechanism by which chronic inflammation promotes carcinogenesis is still unknown. During carcinogenesis the host-mediated anti-tumor activity is suppressed, whereas pro-inflammatory events support tumor growth, angiogenesis, invasion and metastasis. The inflammatory response is mediated by cytokines, which are glycoproteins or soluble proteins and their role in cancer immunity and carcinogenesis has been well established[16-18].
Neuroendocrine tumors express various cytokines and growth-factors. Several pro-inflammatory cytokines have been found in pNETs tissue suggesting their involvement in pNET development[19-21]. Additionally, numerous studies suggested that gastroenteropancreatic-NETs occur more frequently in the environment of chronic inflammation[22-24]. Thus, cytokines such as interleukin 1 (IL-1) poses an important role in neuroendocrine tumors since direct cancer cells to either neuroendocrine differentiation or to development of adenocarcinoma, while exogenously added IL-1 results in a decrease of chromogranin A (CgA) and simultaneous increase in carcinoembryonic antigen (CEA) secretion.
IL-1β is a highly active pro-inflammatory cytokine with multiple biological effects. IL-1β protein levels are related to the intensity of the inflammatory response, and regarding to pancreas, IL-1β is implicated in cancer progression, especially tumor invasiveness, metastasis and angiogenesis[27,28].
The IL-1β gene is located in the IL1 cluster on chromosome 2q and several single nucleotide polymorphisms (SNPs) of this gene influence the regulation of its expression and function have been studied[29-32]. There are two SNPs in the proximal promoter region of the IL-1β gene, -511 C/T and +3954 T/C, which both have been correlated with gastrointestinal cancers, such as gastric, hepatocellular cancer (HCC) and pancreatic cancer[33-36]. Recently, Cigrovski Berkoviç et al reported that the IL-1β -511 SNP contributes to the pNET susceptibility.
We conducted a case-control study to analyze IL-1β polymorphisms as risk factors for pNETs using germline DNA collected in a population-based case-control study of pancreatic cancer [51 pNET cases, 85 PDAC cases, 19 intraductal papillary mucinous neoplasm (IPMN) and 98 healthy controls] conducted in the Athens, Greece and Izmir, Turkey areas.
The case-control study included 51 pNET cases (22 nonfunctional and 29 functional), 85 PDAC cases, 19 IPMN and 98 healthy controls (Table 1). None of the cases had a history of chronic pancreatitis. For subsequent analysis, we excluded cases and controls with known genetic syndromes (e.g., MEN1, MEN2, VHL or TSC). Controls were healthy blood donors with no evidence of inflammation. The diagnosis in all cases was established by standard procedures and confirmed histopathologically either from operatively resected tumors or biopsy tissues, in cases of unresectable tumors. Before commencement of the study, the Ethical committee at the participating centers approved the recruitment protocols. All participants were informed regarding the study, and their written consent was provided.
|Mean age (yr)||59.12||56.31||57.91||58.9|
|Male||51 (60)||20 (39.2)||11 (57.9)||74 (75.5)|
|Female||34 (40)||31 (60.8)||8 (42.1)||24 (24.5)|
|Head||64 (75.3)||19 (37.3)||7 (36.8)|
|Body and tail||21 (24.7)||32 (62.7)||12 (63.2)|
Genomic DNAs were isolated from peripheral ethylenediaminetetraacetic acid-treated blood of patients and healthy controls using the NucleoSpin Blood Kit (Macherey-Nagel, Germany). The IL-1β -511 C/T (rs16944) polymorphism was detected by PCR-RFLP using the set of primers: 5’-TGGCATTGATCTGGTTCATC-3’ and 5’-GTTTAGGAATCTTCCCACTT-3’. The 35 cycles of PCR were carried out at 94 °C for 5 min, 94 °C for 1 min, 58 °C for 40 s and 72 °C for 1 min and the final cycle of 72 °C for 5 min. Amplified PCR products were digested with AvaI for 2 h at 37 °C. The fragments of 189- and 116-bp revealed homozygosity for the C allele, and 305-bp indicated homozygosity for the T allele. The +3954 C/T (rs 1143634) polymorphism was detected with the 5’-TCAGGTGTCCTCGAAGAAATCAAA-3’ and 5’-GGTTTTTTGCTGTGAGTCCC-3’ set of primers and the cycling parameters for that was 94 °C for 5 min, 94 °C for 45 s, 56 °C for 45 s and 72 °C for 45 s and the final cycle of 72 °C for 5 min. After 35 cycles the PCR product were digested for 2 h at 65 °C with TaqI. The fragments of 97- and 85-bp revealed homozygosity for the C allele and on the other hand 182-bp fragments showed homozygosity for the T allele.
Genotype frequencies were compared with the χ2 with Yate’s correction using S-Plus (v. 6.2, Insightful, Seattle, WA). Odds ratios (ORs) and 95%CIs were obtained with GraphPad (v. 3.00, GraphPad Software, San Diego, CA). The P values are all two-sided, and P values of < 0.05 were considered to be significant. Hardy-Weinberg equilibrium was verified by calculating the expected frequencies and numbers and was tested separately in patients and in controls using the goodness-of-fit χ2 test. Haplotype analysis was performed using the http://bioinfo.iconcologia.net/SNPstats software.
The clinicopathological characteristics of the studied population are summarized in Table 1. The genotype frequencies of the IL-1β -511 C/T and +3954 C/T polymorphisms between PDAC, pNET, IPMN patients and controls are given in Table 2. All genotype distributions were in Hardy-Weinberg equilibrium. The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups only showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients (Table 2). However, the presence of the +3954T allele seems to have a protective role in the pNET development since it is found to be over-represented in healthy controls. The haplotype analysis did not reveal any significant association. No significant association was found between genotypes, haplotypes, and clinicopathological data of the patients.
|Controls (n = 98)||PDAC (n = 85)||P; OR (95%CI)||pNET (n = 51)||P; OR (95%CI)||IPMN (n = 19)||P; OR (95%CI)|
|CT||47||44||0.64; 1.18 (0.64-2.16)||31||0.04; 2.23 (1.04-4.81)||10||0.59; 1.56 (0.52-4.65)|
|TT||7||6||1; 1.08 (0.33-3.49)||7||0.04; 3.95 (1.13-13.84)||3||0.16; 3.14 (0.64-15.56)|
|CT + TT||54||50||0.37; 1.36 (0.75-2.44)||38||0.02; 2.38 (1.13-5.02)||13||0.32; 1.76 (0.62-5.03)|
|T allele||61||56||0.74; 1.09 (0.7-1.69)||45||0.03; 1.75 (1.07-2.86)||16||0.19; 1.61 (0.79-3.28)|
|CT||44||28||0.08; 0.57 (0.31-1.07)||16||0.07; 0.49 (0.24-1.03)||10||0.79; 1.28 (0.46-3.54)|
|TT||9||7||0.59; 0.7 (0.24-2.04)||2||0.19; 0.3 (0.06-1.49)||1||1; 0.62 (0.07-5.64)|
|CT + TT||53||35||0.1; 0.59 (0.33-1.07)||18||0.04; 0.46 (0.23-0.93)||11||0.81; 1.18 (0.43-3.15)|
|T allele||62||42||0.16; 0.71 (0.45-1.12)||20||0.03; 0.53 (0.29-0.94)||12||0.85; 1.07 (0.51-2.25)|
PNETs are a rare, heterogeneous group of neuroendocrine tumors. They usually have a better prognosis than the PDACs. The cause of these tumors is not fully understood, but differential expression of proinflammatory cytokines were found in pNET tissues[19-21]. The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only. None significant correlation was found with PDAC and IPMN cases. Although Barber et al, reported that the +3954 C/T polymorphism of the IL-1β gene predisposes to pancreatic cancer; our findings did not reveal any significant association. Additionally, they are partly in agreement with the findings of Cigrovski Berkovic et al, which suggest that there is an association between the IL-1β -511 C/T genotype and the susceptibility to pNET, especially functional pNETs. In our study we did not find any haplotype combination to be statistically associated with the susceptibility to pNETs, neither PDAC nor IMPN cases, but we observed that the +3954T allele is over-represented among healthy controls compared to pNET cases suggesting that this allele might have a protective role in pNET development.
Carcinogenesis in the gastrointestinal tract and pancreas is often associated with chronic inflammation[39-42]. It is known that the carriers of the -511T allele associated with high IL-1β serum levels, and in different type of cancers IL-1β levels correlate with inflammation, worse prognosis and carcinoembrional antigen (CEA) levels, a well-known biomarker of tumor exocrine differentiation[25,43].
Our previous results suggested that TNF-α -1031 polymorphism is associated with the development of pNET and IPMN, and several studies supported that pro-inflammatory cytokines were detected in pNET tissues signifying their etiological involvement[19,44]. Taken these into consideration future studies in larger populations are needed to elucidate the role of cytokines and inflammatory pathway in the sporadic pNET development.
Carcinogenesis in the gastrointestinal tract and pancreas is often associated with chronic inflammation. The study provides evidence of a role of interleukin 1β(IL-1β) -511 C/T genotypes in the pathogenesis of pancreatic neuroendocrine tumors (pNETs).
PNETs are a rare, heterogeneous group of neuroendocrine tumors. They usually have a better prognosis than the pancreatic adenocarcinomas. The cause of these tumors is not fully understood, but differential expression of proinflammatory cytokines were found in pNET tissues. Identifying genetic factors associated basically with pNET incidence may help in the primary prevention of pNET across the globe.
The study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only.
The study contributes to elucidate the role of cytokines and inflammatory pathway in the sporadic pNET development.
PNETs: Pancreatic neuroendocrine tumors; PDACs: Pancreatic adenocarcinomas; IPMN: Intraductal papillary mucinous neoplasm.
This is an interesting study that looks at IL-1β as a potential inflammatory cytokine stimulus for tumour formation in pNETs. While chronic inflammation is known to contribute to carcinogenesis, in the pancreas, this is peculiar to PDAC where association with chronic pancreatitis is not uncommon.
|1.||Vortmeyer AO, Huang S, Lubensky I, Zhuang Z. Non-islet origin of pancreatic islet cell tumors. J Clin Endocrinol Metab. 2004;89:1934-1938. [PubMed] [DOI]|
|2.||Yalcin S, Oyan B, Bayraktar Y. Current medical treatment of pancreatic neuroendocrine tumors. Hepatogastroenterology. 2007;54:278-284. [PubMed] [DOI]|
|3.||Ehehalt F, Saeger HD, Schmidt CM, Grützmann R. Neuroendocrine tumors of the pancreas. Oncologist. 2009;14:456-467. [PubMed] [DOI]|
|4.||Krampitz GW, Norton JA. Pancreatic neuroendocrine tumors. Curr Probl Surg. 2013;50:509-545. [PubMed] [DOI]|
|5.||Rindi G, Wiedenmann B. Neuroendocrine neoplasms of the gut and pancreas: new insights. Nat Rev Endocrinol. 2012;8:54-64. [PubMed] [DOI]|
|6.||Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol Metab Clin North Am. 2011;40:1-18, vii. [PubMed] [DOI]|
|7.||Zikusoka MN, Kidd M, Eick G, Latich I, Modlin IM. The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer. 2005;104:2292-2309. [PubMed] [DOI]|
|8.||Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci. 2004;1014:13-27. [PubMed] [DOI]|
|9.||Yao JC, Eisner MP, Leary C, Dagohoy C, Phan A, Rashid A, Hassan M, Evans DB. Population-based study of islet cell carcinoma. Ann Surg Oncol. 2007;14:3492-3500. [PubMed] [DOI]|
|10.||Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469-1492. [PubMed] [DOI]|
|11.||Fesinmeyer MD, Austin MA, Li CI, De Roos AJ, Bowen DJ. Differences in survival by histologic type of pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2005;14:1766-1773. [PubMed] [DOI]|
|12.||Grötzinger C. Tumour biology of gastroenteropancreatic neuroendocrine tumours. Neuroendocrinology. 2004;80 Suppl 1:8-11. [PubMed] [DOI]|
|13.||Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153-169. [PubMed] [DOI]|
|14.||Algül H, Treiber M, Lesina M, Schmid RM. Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells? Nat Clin Pract Gastroenterol Hepatol. 2007;4:454-462. [PubMed] [DOI]|
|15.||de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer. 2006;6:24-37. [PubMed] [DOI]|
|16.||Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev. 2004;202:275-293. [PubMed] [DOI]|
|17.||Seruga B, Zhang H, Bernstein LJ, Tannock IF. Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer. 2008;8:887-899. [PubMed] [DOI]|
|18.||Błogowski W, Deskur A, Budkowska M, Sałata D, Madej-Michniewicz A, Dąbkowski K, Dołęgowska B, Starzyńska T. Selected cytokines in patients with pancreatic cancer: a preliminary report. PLoS One. 2014;9:e97613. [PubMed] [DOI]|
|19.||Massironi S, Sciola V, Peracchi M, Ciafardini C, Spampatti MP, Conte D. Neuroendocrine tumors of the gastro-entero-pancreatic system. World J Gastroenterol. 2008;14:5377-5384. [PubMed] [DOI]|
|20.||Franko J, Feng W, Yip L, Genovese E, Moser AJ. Non-functional neuroendocrine carcinoma of the pancreas: incidence, tumor biology, and outcomes in 2,158 patients. J Gastrointest Surg. 2010;14:541-548. [PubMed] [DOI]|
|21.||Chan AO, Kim SG, Bedeir A, Issa JP, Hamilton SR, Rashid A. CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene. 2003;22:924-934. [PubMed] [DOI]|
|22.||Klöppel G, Clemens A. The biological relevance of gastric neuroendocrine tumors. Yale J Biol Med. 1996;69:69-74. [PubMed]|
|23.||Le Marc'hadour F, Bost F, Peoc’h M, Roux JJ, Pasquier D, Pasquier B. Carcinoid tumour complicating inflammatory bowel disease. A study of two cases with review of the literature. Pathol Res Pract. 1994;190:1185-1192; discussion 1185-1192. [PubMed] [DOI]|
|24.||Cigrovski Berkovic M, Cacev T, Catela Ivkovic T, Zjacic-Rotkvic V, Kapitanovic S. New insights into the role of chronic inflammation and cytokines in the etiopathogenesis of gastroenteropancreatic neuroendocrine tumors. Neuroendocrinology. 2014;99:75-84. [PubMed] [DOI]|
|25.||Abdul M, Hoosein N. Relationship of the interleukin-1 system with neuroendocrine and exocrine markers in human colon cancer cell lines. Cytokine. 2002;18:86-91. [PubMed] [DOI]|
|26.||Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87:2095-2147. [PubMed]|
|27.||Corbett JA, Sweetland MA, Wang JL, Lancaster JR, McDaniel ML. Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of Langerhans. Proc Natl Acad Sci USA. 1993;90:1731-1735. [PubMed] [DOI]|
|28.||Apte RN, Dotan S, Elkabets M, White MR, Reich E, Carmi Y, Song X, Dvozkin T, Krelin Y, Voronov E. The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions. Cancer Metastasis Rev. 2006;25:387-408. [PubMed] [DOI]|
|29.||di Giovine FS, Takhsh E, Blakemore AI, Duff GW. Single base polymorphism at -511 in the human interleukin-1 beta gene (IL1 beta). Hum Mol Genet. 1992;1:450. [PubMed] [DOI]|
|30.||Pociot F, Mølvig J, Wogensen L, Worsaae H, Nerup J. A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest. 1992;22:396-402. [PubMed] [DOI]|
|31.||Guasch JF, Bertina RM, Reitsma PH. Five novel intragenic dimorphisms in the human interleukin-1 genes combine to high informativity. Cytokine. 1996;8:598-602. [PubMed] [DOI]|
|32.||Chen H, Wilkins LM, Aziz N, Cannings C, Wyllie DH, Bingle C, Rogus J, Beck JD, Offenbacher S, Cork MJ. Single nucleotide polymorphisms in the human interleukin-1B gene affect transcription according to haplotype context. Hum Mol Genet. 2006;15:519-529. [PubMed] [DOI]|
|33.||Haukim N, Bidwell JL, Smith AJ, Keen LJ, Gallagher G, Kimberly R, Huizinga T, McDermott MF, Oksenberg J, McNicholl J. Cytokine gene polymorphism in human disease: on-line databases, supplement 2. Genes Immun. 2002;3:313-330. [PubMed] [DOI]|
|34.||El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398-402. [PubMed] [DOI]|
|35.||Wang Y, Kato N, Hoshida Y, Yoshida H, Taniguchi H, Goto T, Moriyama M, Otsuka M, Shiina S, Shiratori Y. Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology. 2003;37:65-71. [PubMed] [DOI]|
|36.||Barber MD, Powell JJ, Lynch SF, Fearon KC, Ross JA. A polymorphism of the interleukin-1 beta gene influences survival in pancreatic cancer. Br J Cancer. 2000;83:1443-1447. [PubMed] [DOI]|
|37.||Cigrovski Berković M, Catela Ivković T, Marout J, Zjačić-Rotkvić V, Kapitanović S. Interleukin 1β gene single-nucleotide polymorphisms and susceptibility to pancreatic neuroendocrine tumors. DNA Cell Biol. 2012;31:531-536. [PubMed] [DOI]|
|38.||Chourasia D, Achyut BR, Tripathi S, Mittal B, Mittal RD, Ghoshal UC. Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL-1RN*1 (T1) haplotype may protect against the disease. Am J Gastroenterol. 2009;104:2704-2713. [PubMed] [DOI]|
|39.||Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, de Oca J, Capella G, Canzian F. Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. Cancer Res. 2003;63:3560-3566. [PubMed]|
|40.||Theodoropoulos G, Papaconstantinou I, Felekouras E, Nikiteas N, Karakitsos P, Panoussopoulos D, Lazaris ACh, Patsouris E, Bramis J, Gazouli M. Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. World J Gastroenterol. 2006;12:5037-5043. [PubMed] [DOI]|
|41.||Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest. 2007;117:1175-1183. [PubMed] [DOI]|
|42.||Karakaxas D, Gazouli M, Coker A, Agalianos C, Papanikolaou IS, Patapis P, Liakakos T, Dervenis C. Genetic polymorphisms of inflammatory response gene TNF-α and its influence on sporadic pancreatic neuroendocrine tumors predisposition risk. Med Oncol. 2014;31:241. [PubMed] [DOI]|
|43.||Deans DA, Wigmore SJ, Gilmour H, Paterson-Brown S, Ross JA, Fearon KC. Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastro-oesophageal cancer. Br J Cancer. 2006;95:1568-1575. [PubMed] [DOI]|