The Impact Of SNPs In TP53-regulated Pathway Genes In The Risk Of H&N Cancer

Part 1 The impact of SNPs in TP53-regulated pathwaygenes in the risk of H&N cancerTP53-binding protein 1 (TP53BP1)and TP53 interact duringTP53-mediated transcriptional activation and during checkpointactivation in response to DNA damage. Because suboptimal repair oftobacco-induced DNA damage is associated with risk of squamous cellcarcinoma of the head and neck (SCCHN), we hypothesized thatpotentially functional polymorphisms in TP53BP1 and TP53 maycontribute jointly to SCCHN risk. In a case-control study, DNA samplesfrom age-and sex-matched SCCHN patients (n=818) and cancer-freecontrols (n=821)were genotyped for the presence of three variants ofTP53BP1 (T-885G, Glu353Asp, and G1n1136Lys) and three variants ofTP53 (Arg72Pro, PIN3,and MspI).None of these six genetic variantsalone was associated with SCCHN risk. However, the combinedTP53BP1 genotypes were associated with a significant,dose-response- dependent decrease in SCCHN risk among carriers ofTP53Pro72Pro, P53PIN3MM, and P53IN6MM (trend test: P=0.024,P=0.016, and P=0.016, respectively).Furthermore, TP53BP1 varianthaplotype GGC carriers who were also TP53 variant homozygotes had asignificantly lower risk of SCCHN than did P53BP1 haplotype TCA carriers (adjusted odds ratios [95% confidence intervals] of 0.48[(0.25-0.94] for P53Pro72pro, 0.17 [0.04-0.69] for TP53PIN3 MM, and0.16 [0.04-0.65] for TP53PIN6 MM). There was statistical evidence ofinteraction between TP53BP1 and TP53 diplotypes (P=0.017). Together,these data suggest that the protective effects of TP53BP1 variants onSCCHN risk are confined to TP53 variant allele/haplotype carriers.Part 2 Single Nucleotide Polymorphisms at theTP53-Binding or Responsive Promoter Regions of BAXand BCL2 Genes and Risk of Squamous Cell Carcinomaof the Head and NeckTP53,which is a transcriptional factor, functions to induces the BAXexpression by directly binding to the TP53-binding element in the BAXpromoter but inhibits BCL2 promoter-driven transcription through aresponsive region in the BCL2 promoter. Therefore, we hypothesizedthat single nucleotide polymorphisms (SNPs) of BAX and BCL2promoters and the TP53 codon 72 SNP jointly contribute to cancer risk.We tested this hypothesis in a hospital-based case-control study of 814patients 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 the associations between BAX(-248G＞A), BCL2(-938 C＞A), or TP53 codon 72 SNPs and SCCHN risk inthe single-locus analysis, further analyses showed that, among TP53heterozygotes after adjustment for age, sex, and smoking and alcohol status, the BAX AA genotype was associated with an elevated risk ofSCCHN [(OR=6.60, 95% CI=1.38-31.50 compared with the BAX GGgenotype or OR=6.58,95% CI=1.38-31.49 compared to the combinedgenotypes (GG+AG)],whereas BCL2 A variant genotypes wereassociated with a decreased risk of SCCHN (adjusted OR=0.68,95%CI=0.47-0.98 for CA and OR=0.67, 95% CI=0.48-0.95 for AA+CA,respectively) compared with the BCL2 CC genotype. These altered risksappeared to be consistent with the roles of the anti-apoptotic BCL2 andthe pro-apoptotic BAX. Our data suggest that the risk of SCCHN may beassociated with these two SNPs of BAX and BCL2 promoter regions inSCCHN, particularly among TP53 heterozygotes whose tumors are mostlikely in the absence of TP53-LOH.