Affiliation of authors: Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Correspondence to: Professor Dongxin Lin, MD, Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, China (e-mail: dlin{at}public.bta.net.cn)
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ABSTRACT |
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INTRODUCTION |
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FAS (also known as TNFSF6, CD95, or APO-1) is a cell surface receptor that plays a central role in apoptotic signaling in many cell types (46). This receptor interacts with its natural ligand FASL (also known as CD95L), a member of the tumor necrosis factor superfamily, to initiate the death signal cascade, which results in apoptotic cell death (7). An immuno-privileged status for tumors is established via the FAS-mediated apoptosis of tumor-specific lymphocytes (8,9). Decreased expression of FAS and/or increased expression of FASL favors malignant transformation and progression [for a review, see (10)]. In addition, functional germline and somatic mutations in the FAS gene and perhaps also in the FASL gene that impair apoptotic signal transduction are associated with a high risk of cancer (1115). Thus, the FAS/FASL system appears to have a role in the development and progression of cancer.
In human esophageal squamous-cell carcinomas, expression of FAS is lower and expression of FASL is higher than in the corresponding normal tissue, indicating an association between the aberrant expression of FAS and FASL and esophageal squamous-cell carcinoma (1619). In addition, aberrant expression of FAS and FASL occurs early in dysplasia and in carcinoma in situ (17,18) and has been associated with differentiation, invasiveness, and metastasis of cancer cells and with patients survival (16,19). These findings suggest that FAS and FASL are likely to be involved in the initiation and development of esophageal squamous-cell carcinoma. It has been proposed that decreased expression of FAS also decreases the ability of esophageal squamous-cell carcinoma cells to undergo apoptosis, whereas increased expression of FASL may increase the ability of esophageal squamous-cell carcinoma cells to counterattack the immune system by killing FAS-sensitive lymphocytes (16,17).
Single-nucleotide polymorphisms have been identified in the promoter region of the FAS gene (20,21)G or A at position 1377 (FAS 1377G/A) and A or G at position 670 (FAS 670A/G). The FAS 1377A allele and the FAS 670G allele disrupt Sp1 and STAT1 transcription factor binding sites, respectively, and thus diminish promoter activity and decrease FAS gene expression (2022). The promoter of FASL also has a functional single-nucleotide polymorphisma T or C at position 844(FASL 844T/C)that is located in a binding motif for another transcription factor, CAAT/enhancer-binding protein (23). Higher basal expression of FASL is statistically significantly associated more with the FASL 844C allele than with the FASL 844T allele (23).
Because of the role that FAS and FASL play in cancer development and progression and because of their aberrant expression in various types of cancer, we hypothesized that these functional polymorphisms in FAS and FASL are associated with an increased risk of cancer attributable to the reduced expression of FAS and/or the elevated expression of FASL. In this study, we recruited 588 case patients with incident esophageal squamous-cell carcinoma and 648 healthy population control subjects, and we genotyped FAS and FASL for these polymorphisms to test the hypothesis that they are associated with the risk of esophageal squamous-cell carcinoma. In addition, we also evaluated whether the FAS and FASL polymorphisms were associated with the risk of metastasis.
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MATERIALS AND METHODS |
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This casecontrol study consisted of 588 patients with esophageal squamous-cell carcinoma and 648 population control subjects. All subjects were unrelated ethnic Han Chinese and residents in Beijing and the surrounding regions. Patients were recruited between July 20, 1999, and December 20, 2001, at the Cancer Hospital, Chinese Academy of Medical Sciences (Beijing, China). All patients with histologically confirmed esophageal squamous-cell carcinoma were enrolled. There was no sex and age restriction. The response rate for case patients was 94%. Exclusion criteria included previous cancer and previous chemotherapy or radiotherapy. Two hundred forty of the patients were participants in a molecular epidemiologic study of esophageal cancer, as described previously (24). In the present study, we added 348 patients, for a total of 588 patients with esophageal squamous-cell carcinoma. All patients underwent esophagectomy and had detailed metastatic data. The presence or absence of lymph node metastasis was evaluated according to the tumornodemetastasis classification (25) on the basis of postoperative histopathologic examination of esophageal tumor specimens. Control subjects were cancer-free individuals who were randomly selected from a nutritional survey database conducted in Beijing and the surrounding regions between July 28, 1999, and December 12, 2001. The response rate for control subjects was 89%. The characteristics of 360 control subjects were described previously (24). The selection criteria for the control subjects included no individual history of cancer, and control subjects were frequency matched to case patients on the basis of sex and age (±5 years). In this study, we also selected 288 more control subjects from the same database matched to case patients as described above, for a total of 648 control subjects. At recruitment, written informed consent was obtained from each subject, and personal data from each participant regarding demographic characteristics such as sex and age and related risk factors including tobacco smoking were collected via questionnaire. This study was approved by the institutional review board of the Chinese Academy of Medical Sciences Cancer Institute.
Polymorphism Analysis
Genomic DNA was extracted from blood samples of all control subjects and most case patients. Twenty-eight percent of DNA samples from case patients were isolated from surgically resected normal tissues adjacent to the esophageal tumors. Genotypes were determined by polymerase chain reactionbased restriction fragment length polymorphism (PCRRFLP) as described below, which was performed in a blinded manner (i.e., the casecontrol status of participants was unknown to those performing this test). For quality control, a 15% masked, random sample of DNAs prepared from case patients and control subjects was tested twice by different people, and the results were concordant for all of the masked duplicate sets. Genotypes identified by PCRRFLP were confirmed with DNA sequencing.
PCR primers for amplification of the FAS promoter region containing the FAS 1377G/A polymorphism were FasIF 5'-TGTGTGCACAAGGCTGGCGC-3' and FasIR 5'-TGCATCTGTCACTGCACTTACCACCA-3', which produce a 122-base-pair (bp) fragment. To introduce a restriction endonuclease site, we changed the 3' end of primer FasIF from CAC to CGC, which created a BstUI site. Primers for the FAS 670A/G polymorphism were FasIIF 5'-ATAGCTGGGGCTATGCGATT-3' and FasIIR 5'-CATTTGACTGGGCTGTCCAT-3', which produce a 193-bp fragment. PCR primers for amplification of the FASL promoter region containing the FASL 844T/C polymorphism were FASLF 5'-CAGCTACTCGGAGGCCAAG-3' and FASLR 5'-GCTCTGAGGGGAGAGACCAT-3', which produce a 401-bp fragment. These fragments were amplified separately under the following conditions: a 25-µL reaction mixture containing approximately 100 ng of template DNA, 0.5 µM of each primer, all four deoxyribonucleoside 5' triphosphates (each at 0.2 mM), 2.0 mM MgCl2, and 1.0 U of Taq DNA polymerase in 1x reaction buffer (Promega, Madison, WI). The reaction was carried out with an initial melting step of 2 minutes at 94 °C; followed by 35 cycles of 30 seconds at 94 °C, 30 seconds at 62 °C, and 45 seconds at 72 °C; and a final elongation step of 7 minutes at 72 °C.
The restriction endonucleases BstUI, ScrFI, and BsrDI (New England Biolabs, Beverly, MA) were used to distinguish the FAS 1377G/A, FAS 670A/G, and FASL 844T/C polymorphisms, respectively. The restriction endonuclease products were separated on agarose gels containing ethidium bromide. The RFLPs of the three polymorphisms were readily distinguished. BstUI digestion generated the following fragments: FAS 1377G allele, fragments of 104 bp and 18 bp; FAS 1377A allele, a single fragment of 122 bp; FAS 670A allele, a single fragment of 193 bp; and FAS 670G allele, fragments of 136 bp and 57 bp (because an ScrFI site was gained). The FASL 844C allele had a BsrDI restriction endonuclease site that resulted in two fragments of 233 bp and 168 bp, and the T allele lacked this site and so resulted in a single 401-bp fragment.
Statistical Analysis
Pearsons chi-square test was used to examine differences in demographic variables, smoking status, and the genotype distribution of FAS 1377G/A, FAS 670A/G, and FASL 844T/C polymorphisms between case patients and control subjects and between metastatic and nonmetastatic case patients. Associations between polymorphisms and risk of the development and metastasis of esophageal squamous-cell carcinoma were estimated by use of unconditional logistic regression. Smokers were considered current smokers if they smoked up to 1 year before the date of cancer diagnosis or if they smoked up to 1 year 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 less than 1 year 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, moderate, and heavy smokers were categorized by using the 25th and 75th percentile pack-year values of the control subjects as the cut points (i.e., 17 pack-years, 1832 pack-years, and >32 pack-years). Because only 16 case patients and 18 control subjects were ex-smokers, they were combined with current smokers for analysis. All odds ratios (ORs) were adjusted for age, sex, and smoking status or pack-years, where it was appropriate. A P value of less than .05 was used as the criterion of statistical significance, and all statistical tests were two-sided. We tested the null hypotheses of additive and multiplicative genegene and genesmoking interactions and evaluated departures from additive and multiplicative interaction models (26) by including main effect variables and their product terms in the logistic regression model. All analyses were performed with computer programs from Statistical Analysis System (version 6.12; SAS Institute, Cary, NC).
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RESULTS |
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We next investigated whether there was a statistical interaction between the FAS and FASL genotypes that was associated with the risk of esophageal squamous-cell carcinoma (Table 3). Because the two polymorphisms in FAS were tightly linked, only the FAS 1377G/A polymorphism was analyzed. Case patients with the FAS 1377AA genotype were also more likely to carry the FASL 844CC genotype than control subjects with the FAS 1377AA genotype (11.1% versus 3.9%; P<.001). The presence of one FAS 1377AA genotype or one FASL 844CC genotype was associated with an increased risk for esophageal squamous-cell carcinoma (OR = 1.49, 95% CI = 0.93 to 2.39, or OR = 1.97, 95% CI = 1.54 to 2.52, respectively), compared with the lack of such a genotype. However, the presence of both FASL 844CC and FAS 1377AA genotypes was associated with an even higher risk for esophageal squamous-cell carcinoma increase (OR = 4.55, 95% CI = 2.75 to 7.48) (P = .001; test for homogeneity) compared with those who lacked both genotypes. These results indicate that a more than multiplicative interaction exists between the FASL 844CC and FAS 1377AA genotype that is associated with the risk of developing esophageal squamous-cell carcinoma (26).
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DISCUSSION |
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Our results demonstrating an association between the variant FAS and FASL genotypes and the risk of developing esophageal squamous-cell carcinoma are biologically plausible. First, many studies have shown that increasing the expression of FASL and/or decreasing the expression of FAS is a common feature of malignant transformation and an early event associated with the development of most human cancers, including esophageal squamous-cell carcinoma (10,13,14,1619). Second, the investigated polymorphisms in the FAS and FASL genes are functionally important. The FAS 1377G/A and 670A/G polymorphisms occur in the promoter region within the Sp1 and STAT1 transcription factor binding sites, respectively (2022). Because Sp1 is an important transcriptional activator (30) and its ability to bind to the FAS 1377A allele is reduced, decreased expression of FAS in cells carrying the FAS 1377AA genotype was expected (2022). The FASL 844T/C polymorphism is also located in the promoter region of the gene, and basal FASL expression is higher in cells carrying the C allele than in cells carrying the T allele, as measured in a luciferase reporter assay and when expressed in peripheral blood fibrocytes (23). Given the role of FAS and FASL in the development of cancer, one might expect individuals who carry the FAS 1377AA and/or FASL 844CC genotype, and thus have decreased expression of FAS and/or increased expression of FASL over a lifetime, to be at a higher risk for developing cancer. Finally, an association has been reported between the FAS polymorphisms and risk of lymphoproliferative diseases and some cancers. For example, increased risks for acute myeloid leukemia (21), lung cancer (31), and cervical cancer (32) have been associated with FAS 1377G/A or FAS 670A/G polymorphism. Although no study has reported whether the FASL polymorphism is associated with the risk of cancer, the FASL 844CC genotype has been linked to systemic lupus erythematosus (23), an autoimmune disease characterized by accelerated FAS-mediated apoptosis of lymphocytes and monocytes. Thus, these data strongly support our molecular epidemiologic findings that functional polymorphisms influencing the expression of FAS and/or FASL are associated with an increased risk of cancer.
In this study, we also found a greater than multiplicative genegene interaction between the FAS and FASL polymorphisms. This statistical interaction suggests that these two polymorphisms increase the risk of esophageal squamous-cell carcinoma and are likely to be active in the same causal pathway (33). This speculation is biologically reasonable because FAS and FASL are a receptorligand system whose induction of apoptosis requires both FAS and FASL (34). If a cell carries functional polymorphisms in both genes that affect their level of expression, then a greater than additive effect is to be expected. Transformed cells with the FASL 844CC genotype that express a high level of FASL may create an immuno-privileged site by killing cytotoxic immune cells and thus escape host immuno-surveillance; in contrast, decreased FAS expression resulting from a FAS promoter polymorphism may help the transformed cells evade FAS-mediated cell death. Consequently, the presence of both FAS and FASL polymorphisms would be associated with a greater increase of esophageal carcinogenesis than that associated with the presence of either FAS or FASL polymorphism alone.
Our results indicate that FAS and FASL polymorphisms interacted statistically with tobacco smoking. FAS polymorphisms modulated the risk of esophageal squamous-cell carcinoma among smokers but not among nonsmokers, suggesting a geneenvironment interaction. Because smoking is a risk factor for esophageal squamous-cell carcinoma (27,35), such an interaction is not surprising. A higher risk of esophageal squamous-cell carcinoma associated with smoking and a variant FAS genotype (1377AA or 670GG) may be attributed to many preinvasive or transformed esophageal cells resulting from exposure to tobacco carcinogens, which in turn increase the possibility that one of these cells will evade immuno-surveillance to become malignant because of low FAS expression. We found an increased risk associated with the FAS polymorphism in light and moderate smokers but not in heavy smokers (>32 pack-years in this study). This observation may reflect the fact that the genetic effect can be overwhelmed by the environmental effect. In contrast to FAS polymorphisms, the risk for esophageal squamous-cell carcinoma associated with the FASL polymorphism was statistically significantly increased in both smokers and nonsmokers, and the increased risk among smokers depended on the number of pack-years of smoking. A higher risk associated with the FASL polymorphism in nonsmokers than in smokers who smoked for 17 pack years might be attributed to the exposure of nonsmokers to high levels of secondhand smoke. This exposure is very possible because smoking is prevalent and is not restricted in public places in China. The explanation proposed for the interaction between FAS polymorphisms and smoking may also explain the interaction observed between the FASL polymorphism and smoking. Furthermore, because FASL expression can be induced by tobacco smoking (28,29), another hypothesis for the interaction is that, in addition to higher constitutive expression resulting from the FASL 844T/C polymorphism, smoking may induce a higher level of expression from the FASL C allele than from the FASL T allele. Consequently, smoking and carrying the FASL 844CC genotype increase the risk of developing esophageal squamous-cell carcinoma.
In addition to tobacco smoke, other factors such as alcohol consumption, nutritional deficiency, and exposure to certain chemical carcinogens have been associated with risk of esophageal squamous-cell carcinoma in China [for a review, see (36)]. These factors could interact with FAS and/or FASL genotypes or act as potential confounders in our analysis. Unfortunately, our casecontrol study did not collect information on these factors. However, because ethanol and its metabolite acetaldehyde increase the expression of FASL (37,38), an association between the risk of esophageal squamous-cell carcinoma and the interaction between excess alcohol consumption and FAS and/or FASL should be investigated.
Although the loss of FAS expression and the gain of FASL expression has been associated with differentiation, invasiveness, and metastasis of most cancers, including esophageal squamous-cell carcinoma (10,16,19), we did not find a statistically significant association between the FAS and FASL polymorphisms and the histologic differentiation or lymph node metastasis of esophageal squamous-cell carcinoma. These results indicate that the FAS and FASL polymorphisms studied may not have an important role in metastatic disease. However, our data on metastasis are preliminary and are limited because they were obtained at the time of diagnosis and were essentially restricted to lymph node metastasis. Additional studies investigating more detailed clinicopathologic features and clinic outcomes, especially patient survival data, may be required to resolve this issue.
The allele and genotype frequencies of FAS and FASL vary with ethnicity. In this study with 648 healthy control subjects, we found that the FAS 1377A allele frequency was 0.34 and that AA homozygotes accounted for 10.6% of the Han Chinese population studied, compared with around 0.13 and 2%, respectively, among Caucasians from the United Kingdom, Australia, and Italy (21,39,40). In a Japanese study of 104 participants, however, the frequency of the 1377A allele and the percentage of participants with the AA genotype were 0.46 and 24%, respectively (22). A statistically significant difference was also observed for the FAS 670 polymorphism, with the GG genotype frequency being generally higher in Caucasians (21,4042) than in Asians [(43,44) and this study]. We also observed strong linkage disequilibrium between the FAS 1377 and 670 polymorphisms in our study population. Less strong linkage disequilibrium was also suggested in a Japanese population (22) but not in a Caucasian population (21). Distribution of FASL 844T/C polymorphism was reported to be different among African Americans and among American Caucasians, with 844C allele frequencies of 0.18 and 0.64, respectively (23), the latter being similar to that obtained in this study (i.e., 0.68). Ethnic variation in the FAS/FASL genotype distribution warrants additional comparative studies with more participants to confirm our results.
In conclusion, our study provides, to our knowledge, the first evidence that polymorphisms in the promoter region of FAS and FASL are associated with the risk of developing esophageal squamous-cell carcinoma in a Chinese population, although no association with the risk of metastasis was found. The association of FAS and FASL polymorphisms with the risk of esophageal squamous-cell carcinoma displayed a multiplicative genegene interaction and appeared to be influenced by tobacco smoking. These results may also support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis.
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NOTES |
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Supported by grants from the National Natural Science Foundation (grants 39825122 and 39990570), Beijing Municipal Commission of Science and Technology (grant H0209-20030130), and from State Key Basic Research Program (grant G1998051204).
We thank Dr. Fred F. Kadlubar at National Center for Toxicological Research for helpful comments on the manuscript.
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Manuscript received December 19, 2003; revised April 26, 2004; accepted May 20, 2004.
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