Mouse double minute 4 variants modify susceptibility to risk of recurrence in patients with squamous cell carcinoma of the oropharynx

Abstract

Given the crucial role of Mouse double minute 4 (MDM4) oncoprotein in p53 pathway, single nucleotide polymorphisms (SNPs) could serve as such biomarkers for prediction of SCCOP recurrence. Thus, we investigated associations between three tagging putatively functional variants of MDM4, two in the 3' untranslated region of 3' UTR [rs11801299 (NC_000001.10:g.204529084G>A) and rs10900598(NC_000001.10:g.204525568G>T)] and one in intron 1 [rs1380576(NC_000001.10:g.204488278G>C)], and recurrence risk of SCCOP in 1,008 incident patients. A log-rank test and multivariable Cox models were used to assess associations. Patients with MDM4-rs10900598 GT/TT had a worse disease-free survival (DFS) compared with corresponding GG genotype, while those with rs11801299 AG/AA genotypes had a lower recurrence risk than the cases with rs11801299 GG genotype (both log-rank, P < 0.001). Multivariable analysis showed that significantly different recurrence risk were found among patients with MDM4-rs10900598 GT/TT and rs11801299 AG/AA variant genotypes (HR, 2.0, 95% CI, 1.4-2.9 and HR, 0.4, 95% CI, 0.3-0.6, respectively) compared with their corresponding common homozygous genotypes. Furthermore, after combining the risk genotypes of the three SNPs, patients among low-risk group had a significantly lower risk of SCCOP recurrence than those in high-risk group (HR, 0.2, 95% CI, 0.1-0.3). The risk for both individual SNPs or combined risk genotypes was restricted to HPV-positive SCCOP patients. Our findings suggest that the MDM4 polymorphisms may, individually or in combination, confer an independent risk of SCCOP recurrence, particularly in HPV-positive SCCOP patients. However, larger studies are needed to validate our findings.

A genetic variant within MDM4 3′UTR miRNA binding site is associated with HPV16‐positive tumors and survival of oropharyngeal cancer

“…This current study found that MDM4 rs4245739 was associated with tumor HPV16 status in SCCOP. Although we and others have reported associations of some MDM4 genetic variants with risk and outcomes of head and neck cancers or HPV‐associated head and neck cancers, no studies have been focused on this functional polymorphism. Additionally, most of previous studies either had different HPV16 status of study patients or had heterogeneous tumor sites .…”

“…The univariate prognostic analysis was not statistically significant for some variables, while these variables were retained in the main‐effects and final multivariable model because of biological, epidemiological, and clinical significance considerations. We employed the dominant mode of genotype coding a priori for the SNP analysis as done in our previous analyses and publications . The Kaplan‐Meier method was used to compare survival between patients with different genotypes.…”

“…We employed the dominant mode of genotype coding a priori for the SNP analysis as done in our previous analyses and publications. 37,40,41 The Kaplan-Meier method was used to compare survival between patients with different genotypes. We also calculated the log-rank statistic for testing the hypothesis of a difference in survival between genotyping groups.…”

“…Recent studies suggested that the variation in the 3′‐untranslated region (3′‐UTR) of MDM4 can lead to a decreased risk of various malignancies . Although we have previously reported the associations of several genetic variants of MDM4 , including MDM4 rs11801299 and rs10900598 in the 3′‐UTR and rs1380576 in the first intron, with cancer risk and prognosis, their exact functional changes remain unknown. A functional polymorphism of MDM4 rs4245739 in the 3′UTR of this gene has been identified, and creates a target binding site of miRNA‐191, leading to a decreased level of MDM4 protein.…”

Disparities in Head and Neck Cancer: A Case for Chemoprevention with Vitamin D

“…Combined, these miRs presumably down-regulate 157 gene targets, many with well documented roles in cell proliferation, signal transduction, DNA damage response, cancer stemness, adhesion, extracellular matrix (EMT) organization, and genome stability (i.e., MDM4, CDK4, MSH6, XIAP, ETS1, RHOA, SMAD4, POLD3, COL3A1, FGF2, FOXF2, and SOX5). Notably, MDM4 plays a role in regulating p53 and has been linked to cancer recurrence and poor outcomes in HNC patients [89][90][91]. As another example, the transcription of CDK4 is linked to tobacco mediated oral carcinogenesis and acts as a potent cyclin dependent Kinase 4 Regulatory Factor (KRF) and a potential cancer target [92].…”