Genetic variants in p53-related genes confer susceptibility to second primary malignancy in patients with index squamous cell carcinoma of head and neck

Because of their important roles in mediating the stabilization andexpression of p53, we hypothesized that high-risk genotypes of polymorphismsin p53-related genes, including p53, p73, p14^ARF, MDM2and MDM4, may be associated with an increased risk of secondprimary malignancy (SPM) after index squamous cell carcinomaof the head and neck (SCCHN). We analyzed data from a cohort of1283 patients with index SCCHN who were recruited between 1995and 2007 at MD Anderson Cancer Center and followed for SPMdevelopment. Patients were genotyped for nine polymorphisms ofp53-related genes. A log-rank test and Cox models were used tocompare SPM-free survival and risk. Our results demonstratedthat each p53-related polymorphism had a moderate effect onincreased SPM risk, but when we combined risk genotypes of thesenine polymorphisms together, we found that SPM-free survival wassignificantly shorter among risk groups with a greater number ofcombined risk genotypes. SPM risk increased with increasing numberof risk genotypes (P< 0.0001 for trend). Compared with thelow-risk group (0-3 combined risk genotypes), both the mediumrisk(4-5 combined risk genotypes) and high-risk (6-9 combinedrisk genotypes) groups had significantly increased SPM risk [hazardratio (HR): 1.6; 95% confidence interval (CI): 1.0-2.6 and HR:3.0; 95% CI: 1.8-5.0, respectively]. Moreover, such significant associationswere even higher in several subgroups. Our findings suggestthat combined risk genotypes of p53-related genes may jointlymodify SPM risk, especially in patients who are smokers and thosewith index non-oropharyngeal cancers. However, larger studies areneeded to validate our findings.