Mouse double minute 4 (MDM4), a homolog of MDM2, is a key negative regulator of p53, and its amplification or over-expression contributes to carcinogenesis by inhibiting the p53 tumor suppressor activity. We investigated the association between MDM4 polymorphisms and risk of squamous cell carcinoma of the head and neck (SCCHN).
We genotyped three MDM4 tagging polymorphisms, two in the 3′ untranslated region (3′ UTR: rs11801299G>A and rs10900598G>T) and one in intron 1 (rs1380576C>G), in a case-control study of 1,075 non-Hispanic white SCCHN patients and 1,084 cancer-free controls and evaluated their associations with SCCHN risk.
Although none of these three polymorphisms individually had a statistically significant effect on risk of SCCHN, nor did their combined number of putative risk genotypes (i.e., rs11801299GG, rs1380576CG+GG, and rs10900598GG) (OR = 1.16 and 95% CI=0.93–1.45), we found that individuals with 1–3 risk genotypes had statistically significantly increased risk of oropharyngeal cancer (OR = 1.32 and 95% CI = 1.00–1.73), particularly for those with T1–2 stage (OR = 1.40; 95% CI = 1.02–1.94), those with regional lymph node metastases (N1–3) (OR = 1.44; 95% CI = 1.07–1.95), and those with late stages (III and IV) (OR = 1.34; 95% CI = 1.01–1.77).
Our results suggest that the joint effect of MDM4 variants may contribute to the risk of oropharyngeal cancer in non-Hispanic whites. Additional studies are warranted to unravel whether the particular stage distribution of oropharyngeal cancer with the strongest association (T1–2, N1–3, and III–IV) is a possible link with human papillomavirus-related oropharyngeal cancers.