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Clinical Cancer Research 14, 3230, May 15, 2008. doi: 10.1158/1078-0432.CCR-08-0177
© 2008 American Association for Cancer Research
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Cancer Prevention and Susceptibility

Functional Variants in Cell Death Pathway Genes and Risk of Pancreatic Cancer

Ming Yang1, Tong Sun1, Li Wang2, Dianke Yu1, Xuemei Zhang1, Xiaoping Miao1, Junniao Liu1, Dan Zhao1, Hui Li2, Wen Tan1 and Dongxin Lin1

Authors' Affiliations: 1 Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, and 2 Department of Epidemiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Requests for reprints: Dongxin Lin, Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, China. Phone: 86-10-877-88491; Fax: 86-10-677-22460; E-mail: dlin{at}public.bta.net.cn.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 Disclosure of Potential...
 References
 
Purpose: Fas-Fas ligand (FasL)–mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (–1377G->A and –670A->G), FasL (–844T->C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (–652 6N ins->del) and risk of pancreatic cancer.

Experimental Design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated by logistic regression, and all statistical tests were two sided.

Results: We found a significant decrease in risk of pancreatic cancer associated with FasL and CASP8 but not Fas polymorphisms. Compared with noncarriers, the ORs of developing pancreatic cancer for FasL –844CT and TT carriers were 0.73 (95% CI, 0.57-0.94) and 0.35 (95% CI, 0.19-0.63), and for CASP8 –652 6N ins/del and del/del carriers were 0.65 (95% CI, 0.50-0.85) and 0.56 (95% CI, 0.33-0.98), respectively. Gene-gene interaction between the FasL and CASP8 variants further reduced the cancer risk in a multiplicative manner (OR for the presence of both FasL –844TT and CASP8 –652 6N del/del genotype, 0.10; 95% CI, 0.01-0.75). On the other hand, a multiplicative joint effect between the FasL –844CC or CASP8 –652 6N ins/ins genotype and smoking or diabetes mellitus in intensifying risk of pancreatic cancer was also evident.

Conclusions: These results suggest that genetic variations in the death pathway genes FasL and CASP8 are involved in susceptibility to developing pancreatic cancer.

Antitumor T lymphocytes play a pivotal role in immunosurveillance of cancer cells. However, T lymphocytes can also be triggered into an apoptosis process known as activation-induced cell death after activation by tumor-associated or tumor-specific antigens (1). Accumulating evidence shows that activation-induced cell death is one of the important mechanisms responsible for the increased apoptosis rate among tumor-infiltrating lymphocytes; this process may lead to transformed cells escaping elimination by antitumor immunosurveillance and, therefore, contributes to carcinogenesis and cancer progression (2, 3). Activation-induced cell death of T lymphocytes is caused mainly by death receptor–induced apoptotic signaling (4, 5), which is initiated by Fas and Fas ligand (FasL) interaction and consequential activation of caspase-8 (CASP8), an apical caspase in caspase cascade (6, 7). Antigenic stimulation of cancer within the tumor microenvironment can induce tumor-infiltrating lymphocytes to overexpress FasL, and this may lead to suicide and/or fratricide of tumor-infiltrating lymphocytes via Fas-FasL interaction–triggered apoptosis (8). On the other hand, a wide variety of cancers acquire mutations in genes encoding Fas, FasL, and CASP8 (9–12) or reduced expression of Fas and CASP8 but enhanced expression of FasL (13–15). The aberration of this death pathway leads to cancer cells not only resisting the killing of anticancer T lymphocytes but also counterattacking T lymphocytes by expressing FasL. Thus, the Fas-FasL death pathway may play an important role in the development of cancer.

Genetic polymorphisms in the promoter regions of Fas, FasL, and CASP8 have been associated with differential expression levels of these three genes. The Fas –1377G->A and –670A->G polymorphisms are located within the consensus sequences of binding sites for transcriptional factors stimulatory protein 1 (Sp1) and signal transducers and activators of transcription 1 (STAT1), respectively. These genetic polymorphisms have been shown to decrease Fas expression, probably due to the destruction of binding elements for the transcription factors (16, 17). The FasL –844T->C change is located in a binding motif for transcription factor CAAT/enhancer-binding protein β, and a considerably higher basal expression of FasL is associated with the C allele compared with the T allele (18). For the CASP8 gene, a six-nucleotide deletion polymorphism (–652 6N del) has been identified in the promoter that abolishes an Sp1 binding site and is associated with decreased RNA expression in lymphocytes and lower CASP8 activity and activation-induced cell death of T lymphocytes (19). We and other investigators have shown that these polymorphisms in Fas, FasL, and CASP8 are associated with susceptibility to certain cancers (19–28).

Pancreatic cancer is one of the leading causes of cancer-related death in the world (29, 30). Smoking, diabetes mellitus history, and, perhaps, alcohol drinking are risk factors for pancreatic carcinogenesis (31–34). However, only a part of exposed individuals develops pancreatic cancer in their life span, suggesting that genetic susceptibility factors also play a role in pancreatic carcinogenesis. It has been shown that pancreatic cancer cells often present nonfunctional Fas and aberrant expression of FasL, and this mechanism may contribute to the malignant and often rapid course of the disease (35–37). In view of the importance of Fas-FasL–mediated death pathway in pancreatic cancer, we hypothesized that functional polymorphisms in genes involved in this death pathway might confer susceptibility to the cancer. In this study, we did a case-control study in a Chinese population to evaluate the associations of the aforementioned Fas, FasL, and CASP8 variants, alone and in combination, with risk of developing pancreatic cancer. We also analyzed gene-environment interaction between these genetic variants and smoking, drinking, or diabetes mellitus history.


   Materials and Methods
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 Materials and Methods
Results
 Discussion
 Disclosure of Potential...
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Study subjects. This study consisted of 397 incident patients with pancreatic cancer and 907 controls. All subjects were Han Chinese. Patients were recruited between June 2001 and May 2007 at the Peking Union Hospital and Cancer Hospital, Chinese Academy of Medical Sciences, Beijing. All patients with confirmed pancreatic ductal adenocarcinoma were enrolled with a response rate of 94%. The detailed diagnosis of patients was described previously (38). Controls were cancer-free individuals selected from a community cancer-screening program for early detection of cancer conducted in the same regions during the same time period the patients were collected. These controls were randomly selected from a pool of 2,800 individuals on the basis of physical examination. The selection criteria included no individual history of cancer and frequency matching to cases by sex and age (±5 y). The characteristics of part of controls (n = 337) were described previously (38). In the present study, we selected 570 more controls from the same database matched to cases described above, for a total of 907 controls, to increase the statistical power. At recruitment, informed consent was obtained from each subject and each participant was then interviewed to collect detailed information on demographic characteristics, such as sex and age, and related risk factors, such as cigarette smoking, diabetes mellitus history, and alcohol drinking. This study was approved by the institutional review board.

Polymorphism genotyping. Genotypes of Fas –1377G->A, Fas –670A->G, FasL –844T->C, and CASP8 –652 6N indel polymorphisms were determined by PCR-based RFLP assays as described previously (19, 20). All subjects were successfully genotyped. To ensure quality control, genotyping was done without knowledge of case/control status of the subjects, and a 15% random sample of cases and controls was genotyped twice by different persons; the reproducibility was 100%.

Statistical analysis. A {chi}2 test was used to examine the differences in demographic variables, smoking status, drinking status, diabetes mellitus history, and genotype distributions of Fas –1377G->A, Fas –670A->G, FasL –844T->C, and CASP8 –652 6N indel polymorphisms between patients and controls. Associations between genotypes and risk of developing pancreatic cancer were estimated by odds ratios (OR) and their 95% confident intervals (95% CI) computed using the logistic regression model. Smokers were considered current smokers if they smoked up to 1 y before the date of cancer diagnosis or if they smoked up to 1 y before the date of the interview for control subjects. Information was collected on the number of cigarettes smoked per day, the age at which the subjects started smoking, and the age at which ex-smokers stopped smoking. Subjects who never smoked or smoked <1 y before the date of cancer diagnosis for case patients or the date of interview for control subjects were defined as nonsmokers. The number of pack-years smoked was determined as an indication of the cumulative cigarette-dose level [pack-years = (cigarettes per day / 20) x (years smoked)]. Light and heavy smokers were categorized by using the 50th percentile pack-year value of the controls as the cut points (i.e., ≤20 and >20 pack-years). Participants were classified as drinkers if they drank at least twice a week and continuously for at least 1 y during their lifetime; otherwise, they were defined as nondrinkers. All ORs were adjusted for age, sex, smoking, drinking, and diabetes mellitus history, where it was appropriate. We tested the null hypotheses of multiplicative gene-gene, gene-smoking, gene-drinking, and gene-diabetes mellitus history interactions and evaluated departures from multiplicative interaction models (39) by including main-effect variables and their product terms in the logistic regression model. All analyses were done with computer programs from Statistical Analysis System (version 6.12; SAS Institute).


   Results
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 Materials and Methods
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Discussion
 Disclosure of Potential...
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Subject characteristics. No statistically significant differences were found between patients and controls in terms of median age, sex distribution, and drinking status, suggesting that the frequency matching was adequate (Table 1 ). However, smokers were overrepresented in patients compared with controls (36.8% versus 26.4%; P < 0.001) although light or heavy smokers who smoked ≤20 or >20 pack-years were not significantly different (P = 0.671). Moreover, 16.9% of pancreatic cancer patients had diabetes mellitus that was significantly higher than that in controls (7.5%; P < 0.001).


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  		Table 1. Selected characteristics of patients with pancreatic cancer and controls

 
Allelic frequencies and genotype distributions of Fas, FasL, and CASP8 variants. Allele frequencies and genotype distributions of Fas, FasL, and CASP8 in patients and controls are shown in Table 2 . The respective allele frequencies for Fas –1377A, Fas –670G, FasL –844C, and CASP8 –652 6N del were 0.33, 0.38, 0.30, and 0.25 in controls and 0.32, 0.37, 0.22, and 0.19 in patients. All observed genotype frequencies in both controls and patients conform to Hardy-Weinberg equilibrium. Frequencies of FasL –844CC, CT, and TT genotypes among patients differed significantly from those among controls ({chi}2 = 16.60; P < 0.001; df, 2), with the frequency of TT homozygote being significantly higher among controls than among patients (8.7% versus 3.8%; P < 0.001). Similarly, frequencies of the CASP8 –652 6N ins/ins, ins/del, and del/del genotypes were significantly different among patients and controls ({chi}2 = 12.07; P = 0.002; df, 2), with the frequency of the del/del genotype being higher in controls than in patients (7.0% versus 4.5%; P < 0.001). However, the distributions of Fas –1377 and Fas –670 genotypes were not significantly different between patients and controls ({chi}2 = 0.75; P = 0.688 and {chi}2 = 0.02; P = 0.989).


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  		Table 2. Fas, FasL, and CASP8 allelic and genotype frequencies among patients and controls and their association with pancreatic cancer risk

 
Association between individual polymorphism and pancreatic cancer risk. Unconditional logistic regression analysis was used to estimate associations between genotypes of FasL and CASP8, and risk of pancreatic cancer (Table 2). The FasL –844T allele was shown to be protective allele; subjects having the –844TT or –844CT genotype had an OR of 0.35 (95% CI, 0.19-0.63) or 0.73 (95% CI, 0.57-0.94) for developing pancreatic cancer, respectively, compared with subjects having the –844CC genotype, suggesting that this genetic polymorphism acts in an allele dose–dependent manner (trend test; P < 0.0001). Similarly, the odds of having the CASP8 –652 6N del/del or –652 6N ins/del genotype in patients was 0.56 (95% CI, 0.33-0.98) or 0.65 (95% CI, 0.50-0.85) compared with the –652 6N ins/ins genotype, suggesting that the effect of this polymorphism on protecting against pancreatic cancer is dominant (trend test; P = 0.0007). Adjustment for sex, age, smoking, alcohol drinking, and diabetes mellitus history did not significantly change the respective ORs.

Interaction between FasL and CASP8 polymorphisms. Because FasL or CASP8 polymorphism alone was respectively associated with decreased risk of pancreatic cancer, we further investigated whether there was a statistical interaction between FasL and CASP8 genotypes in reducing the risk (Table 3 ). We found that patients that carried the FasL –844TT genotype were also less likely to carry the CASP8 –652 6N del/del genotype than controls (0.3% versus 1.9%; P < 0.001). The presence of the FasL –844TT genotype or CASP8 –652 6N del/del genotype alone was associated with a decreased risk of pancreatic cancer (OR, 0.51; 95% CI, 0.25-1.05 or OR, 0.76; 95% CI, 0.34-1.68, respectively) compared with the absence of such a genotype. However, the presence of both FasL –844TT and CASP8 –652 6N del/del genotypes was associated with an even lower risk of pancreatic cancer (OR, 0.10; 95% CI, 0.01-0.75; P < 0.05, test for homogeneity) compared with the lack of both genotypes. These results clearly indicate a supermultiplicative interaction (39) between the FasL –844TT and CASP8 –652 6N del/del genotypes in reducing pancreatic cancer risk.


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  		Table 3. Risk of pancreatic cancer associated with FasL genotypes by CASP8 genotypes

 
Interaction between genetic polymorphisms and environmental risk factors. We examined whether there exist interactions between FasL or CASP8 genotypes and smoking or drinking, two lifestyle factors known to be associated with pancreatic cancer risk (31, 32). As shown in Table 4 , although the FasL –844CC genotype was associated with increased risk of pancreatic cancer among nonsmokers compared with the –844TT genotype, smokers having this genotype had highest risk, with the OR being 11.85 (95% CI, 4.44–31.57), which is 5-fold greater than the product of the OR for nonsmokers with the –844CC genotype and the OR for smokers with the –844TT genotype (i.e., 2.17 x 1.03 = 2.24). A similar result was also seen for the FasL –844CT genotype, with the joint OR of 3.92 (95% CI, 1.54–9.97) being 2-fold greater than the product of the OR for nonsmokers with the –844CT genotype and the OR for smokers with the –844TT genotype (i.e., 1.63 x 1.03 = 1.68). These results suggest a multiplicative joint effect between the FasL –844 polymorphism and smoking in intensifying pancreatic cancer risk. However, no significant interaction was observed between the CASP8 –652 6N indel polymorphism and smoking although the higher ORs were seen among subjects who smoked and carried the –652 6N ins/ins or ins/del genotype (all P > 0.05 for homogeneity test). No significant effect of ethanol drinking on risk of the cancer related to the genetic polymorphisms was observed (data not shown).


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  		Table 4. Risk of pancreatic cancer associated with FasL or CASP8 genotypes by smoking

 
Diabetes mellitus is another risk factor for pancreatic cancer (33, 34). Therefore, we also investigated whether it has an effect on the risk attributed to the FasL or CASP8 polymorphism (Table 5 ). Multivariate logistic regression analysis showed that subjects who had diabetes mellitus history and carried the FasL –844CC genotype had an OR of 4.62 (95% CI, 2.80-7.64), which is 1.7-fold greater than the product of the OR for subjects without diabetes mellitus history but with the –844CC genotype and the OR for subjects with the –844TT or CT genotype but with diabetes mellitus history. Similar results were evident for the CASP8 –652 polymorphism, where the highest risk was seen among subjects with both diabetes mellitus history and the ins/ins genotype (OR, 4.74; 95% CI, 2.83-7.94). These results show a multiplicative joint effect between FasL and CASP8 variants and diabetes mellitus in susceptibility to the development of pancreatic cancer.


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  		Table 5. Risk of pancreatic cancer associated with FASL or CASP8 genotypes by diabetes history

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
Disclosure of Potential...
 References
 
In this study, we examined whether genetic polymorphisms in three death-receptor pathway genes, Fas, FasL, and CASP8, alone and in combination, are associated with risk of developing pancreatic cancer. On the basis of the analysis of 397 patients and 907 controls, we showed that the functional polymorphisms in the promoters of the FasL (–844T->C) and CASP8 (–652 6N indel) genes have a significant effect on risk of the cancer. These genetic variants display the modifier effects on the risk not only by themselves but also by gene-gene or gene-environment interaction manner. To summarize, both FasL –844T and CASP8 –652 6N del alleles are associated with significantly lower risk for developing pancreatic cancer compared with the FasL –844C and CASP8 –652 6N ins alleles. In addition, the presence of both FasL –844TT and CASP8 –652 6N del/del genotypes showed a multiplicative joint effect in attenuating susceptibility to pancreatic cancer. On the other hand, FasL –844CC and CASP8 –652 6N ins/ins genotypes seem to have joint effects with smoking or diabetes mellitus history on intensifying pancreatic cancer risk.

The tested polymorphisms in the FasL and CASP8 promoters were selected because they functionally affect transcription factor–binding sites and promoter activity. The FasL –844T->C affects a binding motif for transcription factor CAAT/enhancer–binding protein β, and a considerably higher basal expression of FasL is associated with the C allele compared with the T allele (18). The CASP8 –652 6N ins->del polymorphism abolishes an Sp1 binding site and is associated with decreased RNA expression and lower CASP8 activity in T lymphocytes (19). The observations in the present study are, therefore, biologically plausible. Activation-induced cell death of T lymphocytes, which is mediated mainly by the death receptor pathway, may help malignant cells to escape from CTL killing and, therefore, may contribute to cancer development (1–5). We have previously established that the FasL –844C->T and CASP8 –652 6N ins->del changes strongly reduce the expression of FasL and CASP, respectively, and consequentially reduce activation-induced cell death of tumor-specific T lymphocytes in response to malignant cells, which may be an underlying mechanism contributing to more powerful immune surveillance and attenuated susceptibility to the development of multiple types of common cancers among individuals carrying the FasL –844T and/or CASP8 –652 6N del alleles (19, 22, 23). The present study has extended our findings to pancreatic cancer and further supports our hypothesis that functional polymorphisms in the death receptor pathway genes, which may influence an individual's immune status, modify susceptibility to cancer.

Our results in the present study show a multiplicative interaction between FasL –844T and CASP8 –652 6N del variants in attenuating pancreatic cancer risk. It is well known that CASP8-induced caspase cascade resulting in apoptosis of T lymphocytes is triggered upon receipt of signaling from interaction between Fas and FasL (40). If individuals carry both FasL –844T and CASP8 –652 6N del alleles that have reduced FasL and CASP8 expression, it would be expected that their T lymphocytes are much less subject to activation-induced cell death upon stimulation with tumor antigens compared with those carrying only FasL –844T allele or CASP8 –652 6N del allele alone and, therefore, are at the lowest risk for developing pancreatic cancer. This finding is consistent with the proposed model that multiplicative interaction of two alleles often indicates that they act in the same causal pathway (39).

We also observed a greater than multiplicative gene-environment interaction between FasL –844C allele and smoking. Because smoking is an established risk factor for pancreatic cancer (29, 31, 32) and has a destructive effect on human immune responses (41–43), such an interaction is expected. It has been documented that chronic smoking enhances Fas and FasL expression in peripheral blood lymphocytes, which is believed to play a role in the immune impairment in smokers (44, 45). In addition to higher constitutive expression resulting from the FasL –844C allele, smoking may induce a higher level of FasL expression from the FasL –844C allele than from the FasL –844T allele. Consequently, smoking and carrying the FasL –844C allele may have lower immune response to malignant cells and higher risk for developing pancreatic cancer. Alternatively, a higher risk of pancreatic cancer associated with smoking and the FasL –844C allele may be attributed to many preinvasive or transformed pancreatic cells resulting from exposure to tobacco carcinogens, which, in turn, increase the possibility that one of these cells will evade tumor-infiltrating lymphocyte killing to become malignant because of high expression of FasL (36, 37). The gene-environment interaction between FasL –844C allele and smoking observed in the present study is consistent with our previous studies on esophageal cancer and lung cancer among Chinese populations (20, 21).

Another interesting finding in the present study is that we detected a significant interaction between the FasL –844C or CASP8 –652 6N ins allele and diabetes mellitus history in intensifying risk of pancreatic cancer. Although diabetes mellitus is a risk factor for pancreatic cancer (32–34), the reason why there is interaction between FasL or CASP8 polymorphism and diabetes mellitus in risk of pancreatic cancer is not immediately evident. However, it is well established that the death-receptor pathway also plays a vital role in the pathogenesis of diabetes (46–49). Interestingly, it has been shown in a study using bone marrow chimeras and adoptive transfer analysis that FasL expressed on hematopoietic and nonhematopoietic compartments plays nonredundant roles in the pathogenesis of autoimmune diabetes. Mutation of FasL in either compartment interferes with the autoimmune process and prevents the onset of diabetes, but FasL expressed in the hematopoietic compartment is the dominant regulator of T-cell homeostasis (49). The results indicate that pathogenesis of diabetes is dependent on normal FasL expression, whereas only minimal FasL function is required to maintain T-cell homeostasis, which shares the same mechanism with activation-induced cell death of T cells. In addition, a significant association between type II diabetes and a microsatellite in the 3'untranslated region of FasL was reported (48). These findings suggest that genetic variants of FasL and CASP8 may be the common susceptibility factors for both pancreatic cancer and diabetes mellitus and, thus, diabetes mellitus may be a strong modifier for the risk of developing pancreatic cancer associated with the FasL –844C or CASP8 –652 6N ins allele.

In summary, our study shows for the first time that functional FasL and CASP8 polymorphisms are associated with risk of pancreatic cancer. The association displays a manner of multiplicative gene-gene interaction between FasL and CASP8 polymorphisms and gene-environment interaction between these polymorphisms and smoking or diabetes mellitus history. These results are consistent with our initial findings in the previous studies, further supporting the hypothesis that naturally occurring variants in death pathway genes modify cancer susceptibility.


   Disclosure of Potential Conflicts of Interest
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 Abstract
 Materials and Methods
 Results
 Discussion
 Disclosure of Potential...
References
 
The authors declare that they have no competing financial interests.


   Acknowledgments
 
We thank Yuying Liu for her assistance in recruiting the subjects and her technical support.


   Footnotes
 
Grant support: State Key Basic Research Program grant 2004CB518701 (D. Lin) and New Century Excellent Talents in University grant NCET-05-0171 (W. Tan).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: M. Yang and T. Sun contributed equally to this work. D. Lin and W. Tan are equally responsible for this work.

Received 1/22/08; revised 2/16/08; accepted 2/18/08.


   References
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  1. Green DR, Droin N, Pinkoski M. Activation-induced cell death in T cells. Immunol Rev 2003;193:70–81.[CrossRef][Medline]
  2. Chappell DB, Restifo NP. T cell-tumor cell: a fatal interaction? Cancer Immunol Immunother 1998;47:65–71.[CrossRef][Medline]
  3. Yu P, Fu YX. Tumor-infiltrating T lymphocytes: friends or foes? Lab Invest 2006;86:231–45.[CrossRef][Medline]
  4. Maher S, Toomey D, Condron C, Bouchier-Hayes D. Activation-induced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack. Immunol Cell Biol 2002;80:131–7.[CrossRef][Medline]
  5. Aggarwal BB. Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003;3:745–56.[CrossRef][Medline]
  6. Suda T, Takahashi T, Golstein P, Nagata S. Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 1993;75:1169–78.[CrossRef][Medline]
  7. Siegel RM. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol 2006;6:308–17.[CrossRef][Medline]
  8. Griffith TS, Brunner T, Fletcher SM, Green DR, Ferguson TA. Fas ligand-induced apoptosis as a mechanism of immune privilege. Science 1995;270:1189–92.[Abstract/Free Full Text]
  9. Lee SH, Shin MS, Park WS, et al. Alterations of Fas (APO-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res 1999;59:3068–72.[Abstract/Free Full Text]
  10. Mandruzzato S, Brasseur F, Andry G, Boon T, van der Bruggen P. A CASP-8 mutation recognized by cytolytic T lymphocytes on a human head and neck carcinoma. J Exp Med 1997;186:785–93.[Abstract/Free Full Text]
  11. Kim HS, Lee JW, Soung YH, et al. Inactivating mutations of caspase-8 gene in colorectal carcinomas. Gastroenterology 2003;125:708–15.[CrossRef][Medline]
  12. Soung YH, Lee JW, Kim SY, et al. CASPASE-8 gene is inactivated by somatic mutations in gastric carcinomas. Cancer Res 2005;65:815–21.[Abstract/Free Full Text]
  13. Rabinowich H, Reichert TE, Kashii Y, Gastman BR, Bell MC, Whiteside TL. Lymphocyte apoptosis induced by Fas ligand-expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes. J Clin Invest 1998;101:2579–88.[Medline]
  14. O'Connell J, O'Sullivan GC, Collins JK, Shanahan F. The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand. J Exp Med 1996;184:1075–82.[Abstract/Free Full Text]
  15. Crnogorac-Jurcevic T, Efthimiou E, Capelli P, et al. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene 2001;20:7437–46.[CrossRef][Medline]
  16. Huang QR, Morris D, Manolios N. Identification and characterization of polymorphisms in the promoter region of the human Apo-1/Fas (CD95) gene. Mol Immunol 1997;34:577–82.[CrossRef][Medline]
  17. Sibley K, Rollinson S, Allan JM, et al. Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res 2003;63:4327–30.[Abstract/Free Full Text]
  18. Wu J, Metz C, Xu X, et al. A novel polymorphic CAAT/enhancer-binding protein β element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol 2003;170:132–8.[Abstract/Free Full Text]
  19. Sun T, Gao Y, Tan W, et al. A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 2007;39:605–13.[CrossRef][Medline]
  20. Sun T, Miao X, Zhang X, Tan W, Xiong P, Lin D. Polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J Natl Cancer Inst 2004;96:1030–6.[Abstract/Free Full Text]
  21. Zhang X, Miao X, Sun T, et al. Functional polymorphisms in cell death pathway genes FAS and FASL contribute to risk of lung cancer. J Med Genet 2005;42:479–84.[Abstract/Free Full Text]
  22. Sun T, Zhou Y, Li H, et al. FASL –844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer. J Exp Med 2005;202:967–74.[Abstract/Free Full Text]
  23. Zhang B, Sun T, Xue L, et al. Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer. Carcinogenesis 2007;28:1067–73.[Abstract/Free Full Text]
  24. Wang LE, Cheng L, Spitz MR, Wei Q. Fas A670G polymorphism, apoptotic capacity in lymphocyte cultures, and risk of lung cancer. Lung Cancer 2003;42:1–8.[Medline]
  25. Krippl P, Langsenlehner U, Renner W, Köppel H, Samonigg H. Re: polymorphisms of death pathway genes FAS and FASL in esophageal squamous-cell carcinoma. J Natl Cancer Inst 2004;96:1478–9; author reply 1479.[Free Full Text]
  26. Ueda M, Hung YC, Terai Y, et al. Fas gene promoter –670 polymorphism (A/G) is associated with cervical carcinogenesis. Gynecol Oncol 2005;98:129–33.[CrossRef][Medline]
  27. Zhang Z, Wang LE, Sturgis EM, et al. Polymorphisms of FAS and FAS ligand genes involved in the death pathway and risk and progression of squamous cell carcinoma of the head and neck. Clin Cancer Res 2006;12:5596–602.[Abstract/Free Full Text]
  28. Li C, Larson D, Zhang Z, et al. Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma. Pharmacogenet Genomics 2006;16:253–63.[Medline]
  29. Li D, Xie K, Wolff R, et al. Pancreatic cancer. Lancet 2004;363:1049–57.[CrossRef][Medline]
  30. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.[Abstract/Free Full Text]
  31. Qiu D, Kurosawa M, Lin Y, et al. Overview of the epidemiology of pancreatic cancer focusing on the JACC Study. J Epidemiol 2005;15:S157–67.[CrossRef][Medline]
  32. Lu XH, Wang L, Li H, Qian JM, Deng RX, Zhou L. Establishment of risk model for pancreatic cancer in Chinese Han population. World J Gastroenterol 2006;12:2229–34.[Medline]
  33. Chari ST, Leibson CL, Rabe KG, Ransom J, de Andrade M, Petersen GM. Probability of pancreatic cancer following diabetes: a population-based study. Gastroenterology 2005;129:504–11.[CrossRef][Medline]
  34. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004;159:1160–7.[Abstract/Free Full Text]
  35. Ungefroren H, Voss M, Jansen M, et al. Human pancreatic adenocarcinomas express Fas and Fas ligand yet are resistant to Fas-mediated apoptosis. Cancer Res 1998;58:1741–9.[Abstract/Free Full Text]
  36. von Bernstorff W, Glickman JN, Odze RD, et al. Fas (CD95/APO-1) and Fas ligand expression in normal pancreas and pancreatic tumors. Implications for immune privilege and immune escape. Cancer 2002;94:2552–60.[CrossRef][Medline]
  37. Elnemr A, Ohta T, Yachie A, et al. Human pancreatic cancer cells express non-functional Fas receptors and counterattack lymphocytes by expressing Fas ligand: a potential mechanism for immune escape. Int J Oncol 2001;18:33–9.[Medline]
  38. Wang L, Miao X, Tan W, et al. Genetic polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase and risk of pancreatic cancer. Clin Gastroenterol Hepatol 2005;3:743–51.[CrossRef][Medline]
  39. Brennan P. Gene-environment interaction and aetiology of cancer: what does it mean and how can we measure it? Carcinogenesis 2002;23:381–7.[Abstract/Free Full Text]
  40. Ju ST, Panka DJ, Cui H, et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 1995;373:444–8.[CrossRef][Medline]
  41. Zeidel A, Beilin B, Yardeni I, Mayburd E, Smirnov G, Bessler H. Immune response in asymptomatic smokers. Acta Anaesthesiol Scand 2002;46:959–64.[CrossRef][Medline]
  42. Kalra R, Singh SP, Savage SM, Finch GL, Sopori ML. Effects of cigarette smoke on immune response: chronic exposure to cigarette smoke impairs antigen-mediated signaling in T cells and depletes IP3-sensitive Ca(2+) stores. J Pharmacol Exp Ther 2000;293:166–71.[Abstract/Free Full Text]
  43. Geng Y, Savage SM, Razani-Boroujerdi S, Sopori ML. Effects of nicotine on the immune response. II. Chronic nicotine treatment induces T cell anergy. J Immunol 1996;156:2384–90.[Abstract]
  44. Suzuki N, Wakisaka S, Takeba Y, Mihara S, Sakane T. Effects of cigarette smoking on Fas/Fas ligand expression of human lymphocytes. Cell Immunol 1999;192:48–53.[CrossRef][Medline]
  45. Bijl M, Horst G, Limburg PC, Kallenberg CG. Effects of smoking on activation markers, Fas expression and apoptosis of peripheral blood lymphocytes. Eur J Clin Invest 2001;31:550–3.[CrossRef][Medline]
  46. Zhang S, Liu H, Yu H, Cooper GJ. Fas-associated death receptor signaling evoked by human amylin in islet {β}-cells. Diabetes 2007;57:348–56.[CrossRef][Medline]
  47. Allison J, Thomas HE, Catterall T, Kay TW, Strasser A. Transgenic expression of dominant-negative Fas-associated death domain protein in β cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice. J Immunol 2005;175:293–301.[Abstract/Free Full Text]
  48. Nolsøe RL, Hamid YH, Pociot F, et al. Association of a microsatellite in FASL to type II diabetes and of the FAS-670G>A genotype to insulin resistance. Genes Immun 2006;7:316–21.[CrossRef][Medline]
  49. Mohamood AS, Guler ML, Xiao Z, et al. Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically. Am J Pathol 2007;171:97–106.[Abstract/Free Full Text]



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Z. Zhang, H. Xue, W. Gong, M. Wang, L. Yuan, S. Han, and Z. Zhang
FAS promoter polymorphisms and cancer risk: a meta-analysis based on 34 case-control studies
Carcinogenesis, March 1, 2009; 30(3): 487 - 493.
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