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© 2004 Oxford University Press
CORRESPONDENCE |
RESPONSE: Re: Polymorphisms of Death Pathway Genes FAS and FASL in Esophageal Squamous-Cell Carcinoma
Affiliation of authors: Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Correspondence to: 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)
Recently, we reported a statistically significant association between genetic polymorphisms in the death pathway genes FAS and FASL and risk of esophageal squamous-cell carcinoma among the Chinese (1). Krippl et al. now extend the results to breast cancer, showing a similar association between the FAS –1377G>A polymorphism and risk of the cancer among Caucasians. However, they did not observe the same effect for the other two functional polymorphisms, FAS –670A>G and FASL –844C>T. There are several possible explanations for the inconsistent results between their study on breast cancer and our study on esophageal squamous-cell carcinoma.
First, as Krippl et al. point out, the inconsistencies may be the result of the different ethnicities of the study populations. We have noted in our article that the allelic and genotype frequencies of the investigated FAS and FASL polymorphisms vary greatly with ethnicity (2–7). In our study, both FAS variant genotypes were associated with increased risk for esophageal squamous-cell carcinoma because the two polymorphisms were in almost complete linkage disequilibrium (LD; D' = .99; P<.001). However, according to the data presented by Krippl et al., the LD in their study population, if any, seems to be much weaker. Given this difference in LD, the null association with the –670A>G variant in their study suggests that this polymorphism might have no functional effect on cancer; rather, it may be only a genetic tag of the functional –1377G>A polymorphism (or others) in our study population but not in theirs. In this regard, it would be interesting for them to analyze the effect of the –670A>G variant in the context of haplotype with the –1377G>A variant.
Second, the difference in the results for the FASL polymorphism could reflect the different molecular mechanisms in the formation of different cancers. In fact, we also have extended our study to lung cancer and breast cancer, and we have observed a statistically significant association between these polymorphisms in the FAS/FASL system and risk of lung cancer (Zhang X, Miao X, Sun T, Qu S, Xiong P, Tan W, et al.: unpublished results). However, neither the FAS –1377G>A nor the FASL –844C>T variant was associated with breast cancer, which is similar to the observation by Krippl et al., although a statistically significant interaction between these two polymorphisms was observed (odds ratio = 2.64, 95% confidence interval = 1.45 to 4.81 [Xiong P, Miao X, Sun T, Tan W, Zhang X, Lin D: unpublished data]). These results imply that FAS and FASL polymorphisms may be less important in breast carcinogenesis.
Third, other confounding factors, such as ethnically mixed study populations, should also be considered as a potential source of bias. It has been shown that the genotype frequencies of the FAS –670A>G polymorphism in populations defined as Caucasian but with different origins, such as the United Kingdom, The Netherlands, and the United States, are statistically significantly different (3,4,6). Given these findings, caution should be taken in cancer association studies to avoid genetic heterogeneity of the study population. The general categorization of a human population as Caucasian, Asian, or African might not be sufficient for cancer–genetic association studies, especially when the mutations of interest are fairly recent in origin.
In conclusion, although our studies suggest an association of polymorphisms in FAS and FASL with the risk of certain cancers, we agree with the proposal that more studies should be done for comparison.
REFERENCES
1 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.
2 Huang QR, Manolios N. Investigation of the -1377 polymorphism on the Apo-1/Fas promoter in systemic lupus erythematosus patients using allele-specific amplification.Pathology 2000;32:126–30.[CrossRef][ISI][Medline]
3 Sibley K, Rollinson S, Allan JM, Smith AG, Law GR, Roddam PL, et al. Functional FAS promoter polymorphisms are associated with increased risk of acute myeloid leukemia. Cancer Res 2003;63:4327–30.
4 Nelson HH, Kelsey KT, Bronson MH, Mott LA, Karagas MR. Fas/APO-1 promoter polymorphism is not associated with non-melanoma skin cancer. Cancer Epidemiol Biomarkers Prev 2001;10:809–10.
5 Coakley G, Manolios N, Loughran TP Jr, Panayi GS, Lanchbury JS. A Fas promoter polymorphism at position -670 in the enhancer region does not confer susceptibility to Felty’s and large granular lymphocyte syndromes. Rheumatology (Oxford) 1999;38:883–6.
6 Wu J, Alizadeh BZ, Veen TV, Meijer JW, Mulder CJ, Pena AS. Association of FAS (TNFRSF6)-670 gene polymorphism with villous atrophy in coeliac disease. World J Gastroenterol 2004;10:717–20.[Medline]
7 Wu J, Metz C, Xu X, Abe R, Gibson AW, Edberg JC, et al. A novel polymorphic CAAT/enhancer-binding protein beta 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.
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J Natl Cancer Inst 2004 96: 1478-1479.
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