Abstract 881: Polymorphisms of PUMA, a BH3-only pro-apoptotic gene, modify risk of squamous cell carcinoma of head and neck associated with HPV16 infection

Abstract

Abstract PUMA (p53 upregulated modulator of apoptosis) and Noxa (Latin for damage), as well as their common target MCL-1 (myeloid cell leukemia 1), respond to human papillomavirus 16 (HPV16) oncoprotein E6-mediated p53 degradation or E7-mediated pRb inactivation, and therefore may alter cancer susceptibility through the PUMA (Noxa)-MCL1-apoptosis mechanism. In this case-control study of 380 cases and 335 cancer-free matched controls, we evaluated HPV16 seropositivity and two single nucleotide polymorphisms (SNPs) in the promoter region for each gene (rs3810294 and rs2032809 for PUMA, rs4558496 and rs9957673 for Noxa, rs9803935 and rs3738485 for MCL1) to examine their possible associations with risk of squamous cell carcinoma of head and neck (SCCHN). Of the 6 SNPs, both two SNPs of PUMA were significantly associated with 1.5-fold increased SCCHN risk in a dominant model. When we include the HPV16 seropositivity in the model, the risk of SCCHN was significantly increased in an allele-dose effect manner (Ptrend< 0.0001 for each SNP, respectively). Notably, in the site-stratified analysis, oropharyngeal cancer risk was dramatically increased, particularly among minor alleles carriers having the HPV16 L1 seropositivity with OR (95%CI) of 13.8 (5.4-35.5) for rs3810294 and 8.1 (4.3-15.0) for rs2032809 (both Ptrend < 0.0001). These data suggest some synergistic effects between PUMA variants and HPV16 seropositivity on susceptibility to SCCHN, especially in those cases with HPV-related oropharyngeal cancer. Additionally, the modifying effect of PUMA variants on oropharyngeal cancer associated with the HPV16 L1 seropositivity was more predominant in never-smokers, never-drinkers and young subjects. Our results suggest that PUMA promoter polymorphisms, synergistically interacting with HPV16 L1 seropositivity, modify risk of HPV-related oropharyngeal cancer. Further molecular and epidemiologic studies with larger samples are needed to validate our findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 881. doi:10.1158/1538-7445.AM2011-881