Skip Navigation


Carcinogenesis Advance Access originally published online on August 11, 2007
Carcinogenesis 2007 28(9):2008-2012; doi:10.1093/carcin/bgm172
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/9/2008    most recent
bgm172v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chen, K.
Right arrow Articles by Wei, Q.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, K.
Right arrow Articles by Wei, Q.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Single-nucleotide polymorphisms at the TP53-binding or responsive promoter regions of BAX and BCL2 genes and risk of squamous cell carcinoma of the head and neck

Kexin Chen1,4, Zhibin Hu1, Li-E Wang1, Erich M. Sturgis1,2, Adel K. El-Naggar3, Wei Zhang3 and Qingyi Wei1,*

1 Department of Epidemiology
2 Department of Head and Neck Surgery
3 Department of Pathology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA
4 Present address: Department of Epidemiology and Biostatistics, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China

* To whom correspondence should be addessed. Tel: +1 713 792 3020; Fax: +1 713 563 0999; Email: qwei{at}mdanderson.org


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
Tumor protein 53 (TP53), a transcriptional factor, induces expression of the B-cell lymphoma 2-associated X protein (BAX) gene by directly binding to the TP53-binding element in the BAX promoter but inhibits B-cell lymphoma 2 (BCL2) promoter-driven transcription through a responsive region in the BCL2 promoter. Therefore, we hypothesized that single-nucleotide polymorphisms (SNPs) of BAX and BCL2 promoters and the TP53 codon 72 SNP may jointly contribute to cancer risk. We tested this hypothesis in a hospital-based case–control study of 814 patients with squamous cell carcinoma of the head and neck (SCCHN) and 934 cancer-free controls in a US non-Hispanic white population. While there was no evidence of associations between BAX (–248 G>A), BCL2 (–938 C>A) or TP53 codon 72 SNPs and SCCHN risk in single-locus analyses, further analyses showed that, among TP53 heterozygotes after adjustment for age, sex and smoking and alcohol status, the BAX AA genotype was associated with an elevated risk of SCCHN [odds ratio (OR) = 6.60, 95% confidence interval (CI) = 1.38–31.50 compared with the BAX GG genotype or OR = 6.58, 95% CI = 1.38–31.49 compared with the combined genotypes (GG + AG)], whereas BCL2 A variant genotypes were associated with a decreased risk of SCCHN (adjusted OR = 0.68, 95% CI = 0.47–0.98 for CA vs CC and OR = 0.67, 95% CI = 0.48–0.95 for AA vs CA+CC). These altered risks appeared to be consistent with the roles of the anti-apoptotic BCL2 and the pro-apoptotic BAX. Our data suggest that the risk of SCCHN may be associated with these two SNPs of BAX and BCL2 promoter regions, particularly among TP53 heterozygotes. Larger studies are needed to validate these findings.

Abbreviations: BAX, B-cell lymphoma 2-associated X protein; BCL2, B-cell lymphoma 2; CI, confidence interval; LOH, loss of heterozygosity; OR, odds ratio; PCR, polymerase chain reaction; SCCHN, squamous cell carcinoma of the head and neck; SNP, single-nucleotide polymorphism; TP53, tumor protein 53


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Head and neck cancer is the eighth leading cause of cancer death worldwide (1). In 2007, ~40 566 new cases of squamous cell carcinoma of the head and neck (SCCHN) were diagnosed, and the poor survival of patients with SCCHN has not been improved for several decades (2). Whereas tobacco and alcohol are the primary risk factors for SCCHN development (3–5), epidemiological studies suggest an association of SCCHN with genetic susceptibility in the general population (6–8), and recent studies suggest that genetic polymorphisms in cell-cycle control and apoptosis genes may attribute partly to this predisposition (9,10).

Apoptosis is a process of programmed cell death under both normal physiological and pathological conditions. Deficiency in cell apoptosis alters cell homeostasis and leads to carcinogenesis and tumor progression (11). Apoptosis is regulated by different pathways involving a number of genes that either promote or inhibit apoptosis. The best-characterized apoptosis regulators include the anti-apoptotic B-cell lymphoma 2 (BCL2) gene and the pro-apoptotic B-cell lymphoma 2-associated X protein (BAX) gene. The protein products of these two genes physically interact with each other and the relative levels of the two proteins are important determinants of the apoptosis rate (12–14). Therefore, the relative expression of these two genes plays a key role in cellular homeostasis and cancer development. Another master regulator of cellular apoptosis is the tumor suppressor tumor protein 53 (TP53) gene. Research from the last decade has shown that TP53, which is a transcriptional factor, functions to regulate expression of many apoptosis and cell-cycle regulatory genes. The TP53 protein directly binds to the TP53-binding element in the promoter of BAX gene and induces BAX expression (15,16) and TP53 inhibits BCL2 promoter-driven transcription (17). Recently, it was shown that it interacts with Brn-3a (18) that binds to the BCL2 promoter and blocks the Brn-3a-mediated BCL2 gene expression. Therefore, the interaction between TP53 and the promoters of this pair of apoptosis-regulatory genes is probably important for cellular apoptosis.

However, what factors affect this interaction are less clear except that TP53 mutations that abolish the DNA-binding ability may render TP53 incapable of regulating apoptosis. TP53 mutations have been observed in >50% of all human cancers (19) and there is a high frequency of TP53 mutations in many cancer types including SCCHN (19,20). It has been recognized that during tumor development, one copy of chromosome 17p (the second allele), where TP53 resides, is frequently lost [loss of heterozygosity (LOH)], and the other allele is mutated. Thus, in tumor cells, where two copies of the TP53 gene are present, the gene is probably a wild-type, which provides the opportunity to study the role of variants of the TP53 gene in interaction with other genes involved in the carcinogenesis.

The BCL2 gene is located on chromosome 18q21.3. There is only one reported single-nucleotide polymorphism (SNP) (a C-to-A change) in the promoter region, which has been validated by the published allele frequency and genotype data, that locates at nucleotide position –938 (BCL2 –838 C>A, rs2279115) in the promoter region; only one study with a relatively small sample size investigated the role of this SNP in the etiology of prostate cancer and reported a decrease in prostate cancer risk (21). The BAX gene has been mapped to chromosome 19q13.3. Recently, a SNP located within the 5'-untranslated region of the BAX promoter, G –248A (rs4645878), was reported to be associated with both reduced expression of BAX and altered susceptibility to chronic lymphocytic leukemia (22–27). However, there is no report on the association between the risk of SCCHN and this SNP of the BAX gene. These two promoter SNPs in the BAX and BCL2 genes are particularly interesting because they are located within 100 bases from the TP53-binding element in the BAX promoter region and TP53 responsive element in the BCL2 promoter region, respectively. Thus, these SNPs may affect the interaction between the TP53 protein and the TP53-regulated sequences in the promoters.

Another potentially important factor is a well-recognized non-synonymous SNP in the coding region of TP53 that produces two isoforms of TP53 variants that differ at codon 72, TP53Asp72 or TP53Pro72 (rs1042522). This SNP has been shown to influence the risk of a number of cancer types including cervical cancers (28). However, our previous work has showed that this Arg72Pro polymorphism alone was not associated with an increased risk of SCCHN (29).

In this study, we tested two hypotheses: first, that the SNPs of BAX and BCL2 promoters are associated with risk of SCCHN, and second, that the codon 72 SNP of TP53 may modulate the risk of SCCHN associated with the SNPs of BAX and BCL2 promoters. We tested our hypotheses by genotyping two polymorphisms of BAX (–248 G>A) and BCL2 (–838 C>A) promoter regions and one functional polymorphism of TP53 (Arg72Pro) and evaluating their associations with the risk of SCCHN in a case–control study of 814 patients with SCCHN and 934 cancer-free controls in a US non-Hispanic white population.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Study subjects
This study included 814 patients with histologically confirmed incident SCCHN between October 1999 and February 2006, including cancers of the oral cavity, oropharynx, hypopharynx and larynx, identified at the University of Texas M. D. Anderson Cancer Center. The detailed methods of the case–control study have been described elsewhere (30). The patients with second SCCHN primaries, primaries of the nasopharynx or sinonasal tract, primaries outside the upper aerodigestive tract, cervical metastases of unknown origin or histopathologic diagnoses other than squamous cell carcinoma were excluded. All cases were non-Hispanic whites and had not received any treatment at the time of recruitment. The response rate of the eligible cases whom we approached for recruitment was ~95%. The 934 cancer-free subjects we recruited in the same time period were genetically unrelated visitors or companions of patients seen at the University of Texas M. D Anderson Cancer Center clinics and were frequency matched to the cases by age (±5 years), sex and ethnicity. The response rate of the eligible controls whom we approached for recruitment was ~90%. After being asked to sign an informed consent form, all subjects enrolled in the study were interviewed to gather demographic data and history of smoking and alcohol use. Each eligible subject donated 30 ml of blood collected in heparinized tubes to be used for biomarker assays including DNA extraction and genotyping. The research protocol was approved by the University of Texas M. D Anderson Cancer Center Institutional Review Board.

Genotyping
From each blood sample, a leukocyte cell pellet obtained from the buffy coat by centrifugation of 1 ml of whole blood was used for DNA extraction. Genomic DNA was isolated with the QIAGEN DNA Blood Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's instructions. Restriction fragment length polymorphism–polymerase chain reaction (PCR) was used to identify BAX (–248 G>A) and BCL2 (–838 C>A) polymorphisms in the promoter regions. Each PCR was performed in a 25 µl reaction mixture containing ~50 ng of genomic DNA templates, 12.5 pmol of each primer, 0.1 mM of each deoxynucleoside triphosphate, 1x PCR buffer (50 mM KCl, 10 mM Tris–HCl and 0.1% Triton X-100), 1.5 mM MgCl2 and 1.5 U Taq polymerase (Promega Corporation, Madison, WI). The PCR profile consisted of an initial melting step of 96°C for 5 min, 35 cycles of 96°C for 45 s, 56°C for 40 s and 72°C for 30 s and a final extension step of 72°C for 10 min.

For the BAX (–248 G>A) polymorphism in the promoter, the primers (5'-CATTAGAGCTGCGATTGGACCG-3', in which the -2 C was introduced to create a MspI restriction site, and 5'-GCTCCCTCGGGAGGTTTGGT-3') amplified a 109 bp DNA fragment. Then, the PCR product was digested by MspI (New England BioLabs, Beverly, MA) overnight at 37°C. The digested product was separated on a 2.5% NuSieve 3:1 agarose (FMC BioProducts, Rockland, ME) gel with ethidium bromide and photographed with Polaroid film. The wild-type allele (GG) produced two bands (89 and 20 bp); wild-type/variant allele (GA) produced 20, 89 and 109 bp and the variant allele (AA) lacks the MspI restriction site and therefore produces a single 109 bp band (Table I).

For the BCL2 (–838 C>A) polymorphism in the promoter, the primers (5'-CTGCCTTCATTTATCCAGCA-3' and 5'-GGCGGCAGATGAATTACAA-3') amplified a 300 bp DNA fragment. Then, the PCR product was digested by BccI (New England BioLabs, Beverly, MA) overnight at 37°C. The wild-type allele (CC) produced two bands of 189 and 111 bp; wild-type/variant allele (CA) produced three bands of 111, 189 and 300 bp and the variant allele (AA) produced a single 300 bp band (Table I).

For the TP53 (Arg72Pro) polymorphism in the promoter, the primers (5'-CTGCCTTCATTTATCCAGCA-3' and 5'-GGCGGCAGATGAATTACAA-3') amplified a 296 bp DNA fragment. Then, the PCR product was digested by BstUI (New England BioLabs, Beverly, MA) overnight at 60°C. The wild-type allele (GG) produced two bands of 169 and 127 bp); wild-type/variant allele (GC) produced three bands of 127, 169 and 296 bp and the variant allele (CC) produced a single 296 bp band (Table I).


View this table:
[in this window]
[in a new window]

  		Table I. Genotyping assays for the selected polymorphisms

 
PCR was conducted and the results were evaluated without knowledge of the subjects' case–control status. More than 10% of the samples were randomly selected for repeated assays, and the results were 100% concordant.

Statistical analysis
We used the {chi}2 test to compare the differences in frequency distributions of demographic variables, smoking status, alcohol use, each allele and genotype of the BAX, BCL2 and TP53 polymorphisms between the cases and controls. We also tested the Hardy–Weinberg equilibrium of genotype distributions separately for both cases and controls. Additionally, we used unconditional univariate and multivariate logistic regression analyses to examine the associations between the selected SNPs and SCCHN risk by estimating odds ratios (ORs) and 95% confidence intervals (CIs) with and without adjustment for age, ethnicity, smoking status and alcohol use.

We further stratified the genotype data by subgroups of age, sex, smoking status, alcohol use and the selected SNPs and assessed the risk of SCCHN using multivariate logistic regression models. To evaluate interactions between BCL2, BAX and TP53 genotypes in the risk of SCCHN, logistic regression analysis was also used to assess potential interactions by evaluating departures from additive and multiplicative interaction models. All statistical tests were two-sided, a P value of 0.05 was considered significant, and all analyses were performed using the SAS software (version 9.1; SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Characteristics of the study population
We recruited a total of 821 cases and 934 controls for genotyping, but seven cases failed in the genotyping assays. Thus, the final data analysis included 814 cases and 934 controls. The frequency distribution of selected characteristics of the cases and controls is presented in Table II. Because of frequency matching, there was no statistically significant difference in the distributions of age and sex between cases and controls: 57.0 ± 11.0 (mean ± standard deviation) years and 76.2% males for cases and 55.9 ± 11.2 (mean ± standard deviation) years and 75.1% males for controls (P = 0.548 for age and P = 0.589 for sex). Of the 814 cases, 240 (29.5%) had cancers of the oral cavity, 398 (48.9%) of oropharynx, 41 (5.1%) of hypopharynx and 135 (16.6%) of larynx. However, the cases were more likely than the controls to be smokers and drinkers (P < 0.001 for both smoking and alcohol use) (Table II). Therefore, these variables were further adjusted for in the logistic regression analyses.


View this table:
[in this window]
[in a new window]

  		Table II. Frequency distributions of selected variables in SCCHN cases and cancer-free controls

 
Distribution of genotypes and risk estimates
The genotype and allele distributions of the BAX (–248 G>A), BCL2 (–938 C>A) and TP53 Arg72Pro SNPs in the cases and controls are summarized in Table III. The observed genotype frequencies of these three SNPs in the controls were all in agreement with Hardy–Weinberg equilibrium (P = 0.493 for BAX, P = 0.176 for BCL2 and P = 0.458 for TP53). As shown in Table III, we did not find any statistically significant difference in the frequency distributions of the three SNPs between cases and controls [P = 0.625 for BAX (–248 G>A), P = 0.933 for BCL2 (–938 C>A) and P = 0.454 for TP53 Arg72Pro]. In the single-locus analysis, when the BAX GG genotype was used as the reference group, no association was found between the AG and AA variant genotypes and risk of SCCHN (Table III); similarly, when the BCL2 CC and TP53 Arg/Arg genotypes were used as the references, no BCL2 and TP53 variant genotypes were associated with a significantly increased risk of SCCHN (Table III). In further stratification analysis, we combined the variant genotypes [i.e. BAX (AG + AA), BCL2 (AC + AA) and TP53 (Arg/Pro + Pro/Pro) genotypes] to avoid small numbers in the subgroups. Overall, there was no association between these three combined variant genotypes and risk of SCCHN (Table III) or was any association between these genotypes and SCCHN risk in the subgroups stratified by age, sex, smoking and alcohol use (data not shown).


View this table:
[in this window]
[in a new window]

  		Table III. Logistic regression analysis of associations between BAX, BCL2 and TP53 polymorphisms and risk of SCCHN

 
Gene–gene interaction between BAX, BCL2 and TP53 genotypes
Because we did not find any association in the single-locus analysis, we then tested the hypothesis that BAX, BCL2 and TP53 variant genotypes might jointly alter SCCHN risk. We first stratified one SNP distribution by the other SNP and then evaluated the association between any of the polymorphisms of BAX (–248 G>A), BCL2 (–938 C>A) and P53 (Arg72Pro) and cancer risk among each SNP subgroup (Table IV). The results showed that, among TP53 heterozygotes, there was a significant increase in risk of SCCHN associated with the BAX homozygous variant genotype (AA), either compared with BAX homozygous common genotype (GG) or with combined genotypes (GG + AG) (adjusted OR = 6.58, 95% CI = 1.38–31.49 and OR = 6.60, 95% CI = 1.38–31.50, respectively). In contrast, among the same TP53 heterozygotes, there was a significant decrease in risk of SCCHN associated with both BCL2 heterozygous (AC) and combined variants genotypes (AC + AA) (adjusted OR = 0.68, 95% CI = 0.47–0.98 and OR = 0.67, 95% CI = 0.48–0.95, respectively) compared with the BCL2 homozygous common genotype (CC). These associations were not observed among carriers of other TP53 genotypes (Table IV) nor was an association between cancer risk and any of subgroups of the BCL2 genotypes stratified by the BAX genotypes (Table V). However, further analyses did not find any evidence of potential multiplicative and additive gene–gene and gene–environment interactions among BAX, BCL2 and TP53 variant genotypes, age, sex, smoking status and alcohol use (data not shown).


View this table:
[in this window]
[in a new window]

  		Table IV. Stratified analysis of the association between BAX and BCL2 polymorphisms and SCCHN risk by TP53 genotypes

 


View this table:
[in this window]
[in a new window]

  		Table V. Stratified analysis of the association between BCL2 polymorphisms and SCCHN risk by BAX genotypes

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
In this hospital-based case–control study, we assessed jointly the effects of functional SNPs of BAX (–248 G>A), BCL2 (–938 C>A) and TP53 Arg72Pro on the risk of SCCHN in a US non-Hispanic white population, because the two functional SNPs of the BAX and BCL2 promoters are in the proximal region of sequences that are regulated by the TP53 transcriptional factor. Although our single-locus analysis did not reveal any significant associations between these functional SNPs and SCCHN risk after adjustment for age, sex and smoking and alcohol status, further analyses showed that among TP53 heterozygotes, the BCL2 A variant genotypes appeared to be protective against SCCHN risk, whereas the BAX AA variant genotype exhibited an elevated risk of SCCHN; however, no joint effect was observed between BCL2 and BAX SNPs.

Although these subgroup findings may have been due to chance, as a result of multiple tests, they may reveal some biological interaction between TP53 and its two key effectors, BAX and BCL2. TP53, as a guardian of the genome, regulates cellular apoptosis by directly binding to the promoter elements and activating transcription of a number of apoptosis-regulatory genes, including BAX (31–33). TP53 has also been shown to indirectly inhibit the BCL2 transcription activation through a direct interaction between TP53 with an apoptosis-blocking protein, Brn-3a (18,34).

It was not immediately apparent why our data showed a specific association between the SNP at either of the BAX or BCL2 promoter regions and risk of SCCHN only among TP53 codon 72 heterozygotes. Although we did not have sequencing data on tumor mutations and LOH to unravel their relationship with the codon 72 SNP, a study of the correlation among mutations, LOH and the codon 72 SNP of TP53 in SCCHN has been reported, in which the overall TP53-LOH rate was 45.2% among 42 tumors, but the TP53-LOH rate was low (14.3%) among the Arg72Pro heterozygotes, compared with 33.3% and 64% among the Arg72Arg and Pro72Pro homozygotes, respectively (35). Pertinent to our current study, it is likely that only when the wild-type TP53 was present, the effect of the regulation on BCL2 or BAX by the TP53 codon 72 SNP can be adequately manifested. We believe this regulatory hierarchy accounts for our observation that the association of SNPs in the BAX and BCL2 promoters with risk of SCCHN is only observed in TP53 codon 72 heterozygotes whose tumors are most likely in the absence of TP53-LOH. Therefore, it is not surprising that our analyses did not reveal an association between BCL2 (–938 C>A) or BAX (–248 G>A) polymorphisms and the risk of SCCHN in TP53 homozygotes for codon 72, because any association is likely be abolished by the TP53-LOH and mutations in the tumors of such individuals.

It can be speculated that the A variant genotypes at the position –938 of the BCL2 promoter may render a better interaction with TP53, leading to a decrease in the BCL2 expression, an up-regulated programmed cell death or reduced longevity of transformed cells, and thus a subsequent decrease in the risk of SCCHN. Likewise, our data also showed that there was an increased risk of SCCHN associated with the BAX (–248 G>A) polymorphism among the TP53 heterozygotes. This may be due to the weakening of TP53 interaction with the –248AA genotype, leading to a decrease in the expression of pro-apoptotic BAX gene in the cells and a high risk of SCCHN. Such hypotheses may help explain the absence of LOH in the tumors of TP53 codon 72 heterozygotes (35) and provide a support for an unknown molecular mechanism of carcinogenesis of cells heterozygous for the TP53 codon 72.

Until now, there are only a few reports on the association between BCL2 (–938 C>A) or BAX (–248 G>A) polymorphisms and risk of cancer, mostly chronic lymphocytic leukemia (22–27) but not solid tumors. Several studies have reported that the SNP located within the 5'-untranslated region of the BAX promoter (-248 G>A), was associated with reduced expression of BAX and increased susceptibility to chronic lymphocytic leukemia (25). Recently, a study has examined the effect of the promoter SNP of the BCL2 gene on prostate cancer susceptibility in three ethnic populations, African-Americans, Jamaicans and European Americans. This study showed that the heterogynous BCL2 genotype was associated with a decreased prostate cancer risk among the European Americans, although the study size (n = 218) was relatively small (21). To the best of our knowledge, our study is the first report showing an association between BAX and BCL2 promoter SNPs and the risk of SCCHN stratified by the TP53 codon 72 genotypes. We further demonstrated that in solid tumors where TP53 mutations are frequent, stratification by the TP53 codon 72 SNP as a surrogate for LOH and mutation status is necessary to reveal this association.

In conclusion, our data from a relatively large case–control study provide evidence that the SNPs in the promoter regions of BAX and BCL2 may affect their regulation by TP53 and their association with risk of SCCHN, particularly in TP53 heterozygotes. Because this is a hospital-based case–control study and the findings of subgroups are limited due to small sample sizes in the strata, our results need to be validated by larger, preferably prospective, studies, in which the tumors from those who are heterozygous for the TP53 codon 72 SNP should be examined for the evidence of lacking TP53-LOH.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
National Institutes of Health (ES11740 and CA100264) to Q.W; The University of Texas M. D. Anderson Cancer Center Support Grant (CA16672).


   Acknowledgments
 
We thank Margaret Lung, Kathryn Patterson and Leanel Fairly for their assistance in recruiting the subjects and Yawei Qiao, Kejing Xu, Jianzhong He and Xiaodong Zhai for their technical assistance.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

  1. Ragin CC, et al. The epidemiology and risk factors of head and neck cancer: a focus on human papillomavirus. J. Dent. Res. (2007) 86:104–114.[Abstract/Free Full Text]
  2. Jemal A, et al. Cancer statistics, 2007. CA Cancer J. Clin. (2007) 57:43–66.[Abstract/Free Full Text]
  3. Paz-Elizur T, et al. Reduced repair of the oxidative 8-oxoguanine DNA damage and risk of head and neck cancer. Cancer Res. (2006) 66:11683–11689.[Abstract/Free Full Text]
  4. Yang M, et al. Effects of ERCC1 expression in peripheral blood on the risk of head and neck cancer. Eur. J. Cancer Prev. (2006) 15:269–273.[CrossRef][Web of Science][Medline]
  5. Zhang Z, et al. Polymorphisms of methionine synthase and methionine synthase reductase and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Cancer Epidemiol. Biomarkers Prev. (2005) 14:1188–1193.[Abstract/Free Full Text]
  6. Ho T, et al. Epidemiology of carcinogen metabolism genes and risk of squamous cell carcinoma of the head and neck. Head Neck (2007) 29:682–699.[CrossRef][Web of Science][Medline]
  7. Gattas GJ, et al. Genetic polymorphisms of CYP1A1, CYP2E1, GSTM1, and GSTT1 associated with head and neck cancer. Head Neck (2006) 28:819–826.[CrossRef][Web of Science][Medline]
  8. Oude Ophuis MB, et al. Polymorphisms of the glutathione S-transferase P1 gene and head and neck cancer susceptibility. Head Neck (2003) 25:37–43.[CrossRef][Web of Science][Medline]
  9. Li G, et al. Genetic polymorphisms of p21 are associated with risk of squamous cell carcinoma of the head and neck. Carcinogenesis (2005) 26:1596–1602.[Abstract/Free Full Text]
  10. Li G, et al. Association of a p73 exon 2 G4C14-to-A4T14 polymorphism with risk of squamous cell carcinoma of the head and neck. Carcinogenesis (2004) 25:1911–1916.[Abstract/Free Full Text]
  11. Tang DG, et al. Target to apoptosis: a hopeful weapon for prostate cancer. Prostate (1997) 32:284–293.[CrossRef][Web of Science][Medline]
  12. Cory S, et al. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer (2002) 2:647–656.[CrossRef][Web of Science][Medline]
  13. Kim HJ, et al. 4-Acetyl-12,13-epoxyl-9-trichothecene-3, 15-diol from Isaria japonica mediates apoptosis of rat bladder carcinoma NBT-II cells by decreasing anti-apoptotic Bcl-2 expression and increasing pro-apoptotic Bax expression. Am. J. Chin. Med. (2004) 32:377–387.[CrossRef][Web of Science][Medline]
  14. Loro LL, et al. Oral squamous cell carcinoma is associated with decreased bcl-2/bax expression ratio and increased apoptosis. Hum. Pathol. (1999) 30:1097–1105.[CrossRef][Web of Science][Medline]
  15. Thornborrow EC, et al. A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes. Oncogene (2002) 21:990–999.[CrossRef][Web of Science][Medline]
  16. Miyashita T, et al. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell (1995) 80:293–299.[CrossRef][Web of Science][Medline]
  17. Zhan Q, et al. Inhibitory effect of Bcl-2 on p53-mediated transactivation following genotoxic stress. Oncogene (1999) 18:297–304.[CrossRef][Web of Science][Medline]
  18. Budhram-Mahadeo V, et al. p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J. Biol. Chem. (1999) 274:15237–15244.[Abstract/Free Full Text]
  19. Hollstein M, et al. p53 mutations in human cancers. Science (1991) 253:49–53.[Abstract/Free Full Text]
  20. Andrews GA, et al. Mutation of p53 in head and neck squamous cell carcinoma correlates with Bcl-2 expression and increased susceptibility to cisplatin-induced apoptosis. Head Neck (2004) 26:870–877.[CrossRef][Web of Science][Medline]
  21. Kidd LR, et al. Germline BCL-2 sequence variants and inherited predisposition to prostate cancer. Prostate Cancer Prostatic Dis. (2006) 9:284–292.[CrossRef][Web of Science][Medline]
  22. Fegan C, et al. The role of the bax gene polymorphism G(-248)A in chronic lymphocytic leukemia. Leukemia (2006) 20:1460–1461.[CrossRef][Web of Science][Medline]
  23. Nuckel H, et al. Bax gene G(-248)A promoter polymorphism and chronic lymphocytic leukemia: lack of association with incidence, disease stage and progression-free survival. Leukemia (2006) 20:724.[CrossRef][Web of Science][Medline]
  24. Moshynska O, et al. Molecular detection of the G(-248)A BAX promoter nucleotide change in B cell chronic lymphocytic leukaemia. Mol. Pathol. (2003) 56:205–209.[Abstract/Free Full Text]
  25. Saxena A, et al. Association of a novel single nucleotide polymorphism, G(-248)A, in the 5'-UTR of BAX gene in chronic lymphocytic leukemia with disease progression and treatment resistance. Cancer Lett. (2002) 187:199–205.[CrossRef][Web of Science][Medline]
  26. Skogsberg S, et al. The G(-248)A polymorphism in the promoter region of the Bax gene does not correlate with prognostic markers or overall survival in chronic lymphocytic leukemia. Leukemia (2006) 20:77–81.[CrossRef][Web of Science][Medline]
  27. Starczynski J, et al. Common polymorphism G(-248)A in the promoter region of the bax gene results in significantly shorter survival in patients with chronic lymphocytic leukemia once treatment is initiated. J. Clin. Oncol. (2005) 23:1514–1521.[Abstract/Free Full Text]
  28. Rosenthal AN, et al. p53 codon 72 polymorphism and risk of cervical cancer in UK. Lancet (1998) 352:871–872.[CrossRef][Web of Science][Medline]
  29. Shen H, et al. P53 codon 72 polymorphism and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Lett. (2002) 183:123–130.[CrossRef][Web of Science][Medline]
  30. Shen H, et al. An intronic poly (AT) polymorphism of the DNA repair gene XPC and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Res. (2001) 61:3321–3325.[Abstract/Free Full Text]
  31. Cobb LJ, et al. Phosphorylation by DNA-dependent protein kinase is critical for apoptosis induction by insulin-like growth factor binding protein-3. Cancer Res. (2006) 66:10878–10884.[Abstract/Free Full Text]
  32. Fortin A, et al. APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J. Cell Biol. (2001) 155:207–216.[Abstract/Free Full Text]
  33. Kawamata H, et al. Oncogenic mutation of the p53 gene derived from head and neck cancer prevents cells from undergoing apoptosis after DNA damage. Int. J. Oncol. (2007) 30:1089–1097.[Web of Science][Medline]
  34. Smith MD, et al. Bcl-2 transcription from the proximal P2 promoter is activated in neuronal cells by the Brn-3a POU family transcription factor. J. Biol. Chem. (1998) 273:16715–16722.[Abstract/Free Full Text]
  35. Schneider-Stock R, et al. Retention of the arginine allele in codon 72 of the p53 gene correlates with poor apoptosis in head and neck cancer. Am. J. Pathol. (2004) 164:1233–1241.[Abstract/Free Full Text]
Received April 20, 2007; revised June 12, 2007; accepted July 20, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Ann OncolHome page
G. F. Lehnerdt, P. Franz, A. Bankfalvi, S. Grehl, A. Kelava, H. Nuckel, S. Lang, K. W. Schmid, W. Siffert, and H. S. Bachmann
The regulatory BCL2 promoter polymorphism (-938C>A) is associated with relapse and survival of patients with oropharyngeal squamous cell carcinoma
Ann. Onc., June 1, 2009; 20(6): 1094 - 1099.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
28/9/2008    most recent
bgm172v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (3)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chen, K.
Right arrow Articles by Wei, Q.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chen, K.
Right arrow Articles by Wei, Q.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?