Polymorphic TP53BP1 and TP53 gene interactions associated with risk of squamous cell carcinoma of the head and neck

Purpose: Tumor protein 53-binding protein 1 (TP53BP1) and TP53 interact during TP53-mediated transcriptional activation and during checkpoint activation in response to DNA damage. Because suboptimal repair of tobacco-induced DNA damage is associated with risk of squamous cell carcinoma of the head and neck (SCCHN), we hypothesized that potentially functional polymorphisms in TP53BP1 and TP53 may contribute jointly to SCCHN risk. Experimental Design: In a case-control study, DNA samples from age- and sex-matched SCCHN patients (n = 818) and cancer-free controls (n = 821) were genotyped for the presence of three variants of TP53BP1 (T-8856, Glu(353)Asp, and Gln(1136)Lys) and three variants of TP53 (Arg(72)Pro, PIN3, and Mspl). Multivariate logistic regression was used to assess the adjusted odds ratios (OR) and 95% confidence intervals (95% Cl). Results: Although none of these six genetic variants alone was associated with SCCHN risk, the combined TP53BP1 genotypes were associated with a significant, dose response-dependent decrease in SCCHN risk among carriers of TP53Pro(72)Pro, TP53PIN3del/del, and TP53Msp1AA genotypes (trend test: P = 0.024, 0.016, and 0.016, respectively). Furthermore, TP53BP1 variant haplotype GGC carriers who were also TP53 variant homozygotes had a significantly lower risk of SCCHN than did TP53BP1 haplotype TCA carriers (adjusted OR, 0.48; 95% Cl, 0.25-0.94 for TP53Pro(72)Pro; adjusted OR, 0.17; 95% Cl, 0.04-0.69 for TP53PIN3del/de; and adjusted OR, 0.16; 95% Cl, 0.04-0.65 for TP53Msp1AA). There was statistical evidence of interaction between TP53BP1 and TP53 diplotypes (P = 0.017). Conclusion: Our data suggest that TP53BP1 variants may have protective effects on SCCHN risk but such effects were confined to TP53 variant allele/haplotype carriers.