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

ABSTRACT: Because of their important roles in mediating the stabilization and expression of p53, we hypothesized that high-risk genotypes of polymorphisms in p53-related genes, including p53, p73, p14(ARF), MDM2 and MDM4, may be associated with an increased risk of second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). We analyzed data from a cohort of 1283 patients with index SCCHN who were recruited between 1995 and 2007 at MD Anderson Cancer Center and followed for SPM development. Patients were genotyped for nine polymorphisms of p53-related genes. A log-rank test and Cox models were used to compare SPM-free survival and risk. Our results demonstrated that each p53-related polymorphism had a moderate effect on increased SPM risk, but when we combined risk genotypes of these nine polymorphisms together, we found that SPM-free survival was significantly shorter among risk groups with a greater number of combined risk genotypes. SPM risk increased with increasing number of risk genotypes (P < 0.0001 for trend). Compared with the low-risk group (0-3 combined risk genotypes), both the medium-risk (4-5 combined risk genotypes) and high-risk (6-9 combined risk genotypes) groups had significantly increased SPM risk [hazard ratio (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 associations were even higher in several subgroups. Our findings suggest that combined risk genotypes of p53-related genes may jointly modify SPM risk, especially in patients who are smokers and those with index non-oropharyngeal cancers. However, larger studies are needed to validate our findings.

SUBMITTER: Jin L

PROVIDER: S-EPMC3697893 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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

Jin Lei L Sturgis Erich M EM Zhang Yang Y Huang Zhigang Z Wei Peng P Guo Wei W Wang Zhongqiu Z Wei Qingyi Q Song Xicheng X Li Guojun G

Carcinogenesis 20130318 7

Because of their important roles in mediating the stabilization and expression of p53, we hypothesized that high-risk genotypes of polymorphisms in p53-related genes, including p53, p73, p14(ARF), MDM2 and MDM4, may be associated with an increased risk of second primary malignancy (SPM) after index squamous cell carcinoma of the head and neck (SCCHN). We analyzed data from a cohort of 1283 patients with index SCCHN who were recruited between 1995 and 2007 at MD Anderson Cancer Center and followe ...[more]

PMID: 23508638

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Project description:BACKGROUND:p14(ARF) , an alternate reading frame (ARF) product of the cyclin-dependent kinase inhibitor 2A locus, plays a critical role in crosstalk between the tumor protein 53 (p53) and retinoblastoma (Rb) pathways and in cellular anticancer mechanisms. Therefore, the authors of this report investigated the association between single nucleotide polymorphisms (SNPs) of the p14(ARF) gene and the risk of developing a second primary malignancy (SPM) after an index squamous cell carcinoma of the head and neck (SCCHN). METHODS:The log-rank test and Cox proportional hazards models were used to assess the association of 2 p14(ARF) SNPs (reference SNP [rs]3731217 and rs3088440) with SPM-free survival and with the risk of developing an SPM among 1287 patients who had SCCHN. RESULTS:Patients with either p14(ARF) variant genotypes of the 2 polymorphisms had a significantly reduced SPM-free survival compared with patients with no variant genotypes (log-rank test; P = .006). Compared with the p14(ARF) thymine-thymine (TT) and guanine-guanine (GG) genotypes, the variant genotypes of p14(ARF) TG/GG and guanine-adenine (GA)/AA were associated with a significantly moderately increased risk of developing an SPM (p14(ARF) rs3731217: adjusted hazard ratio [aHR], 1.48; 95% confidence interval [CI], 1.00-2.19; p14(ARF) rs3088440: aHR, 1.61; 95% CI, 1.07-2.43). Moreover, after combining the variant genotypes of the 2 SNPs, patients who had variant genotypes were at significantly greater risk of developing an SPM compared with patients who had no variant genotypes (aHR, 3.07; 95% CI, 1.54-6.12), and the risk was particularly pronounced in several subgroups. CONCLUSIONS:The current results suggested that there is a modestly increased risk of developing an SPM after an index SCCHN with each p14(ARF) polymorphism, and there is an even greater risk of developing an SPM for patients with combined variant genotypes of the 2 SNPs. Therefore, p14(ARF) polymorphisms may be susceptible markers of the risk of developing an SPM in patients with SCCHN.

Project description:BackgroundChronic inflammation is a risk factor for head and neck squamous cell carcinoma (HNSCC) and other diseases. Prostanoid receptors are clearly involved in the development of many types of cancer. However, their role is not simple and is poorly understood in HNSCC.MethodsMethylation profiles of prostanoid receptor family genes were generated for tumour samples obtained from 274 patients with HNSCC, including 69 hypopharynx, 51 larynx, 79 oral cavity, and 75 oropharynx tumour samples, by quantitative methylation-specific PCR. Promoter methylation was then evaluated with respect to various clinical characteristics and patient survival.ResultsThe mean number of methylated genes per sample was 2.05 ± 2.59 (range 0 to 9). Promoters of PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, and TBXA2R were methylated in 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, and 11.3% of the samples, respectively. Methylation indices for prostanoid receptor family genes tended to be higher as the number of TET methylation events increased. Patients with 5-9 methylated genes had a significantly lower survival rate than that of patients with 0-4 methylated genes (log-rank test, P= 0.007). In multivariate analyses, PTGDR1 methylation was most highly correlated with recurrence in patients with hypopharyngeal cancer (P = 0.014). A similar correlation was observed for PTGER4 in patients with laryngeal cancer (P = 0.046). Methylation of the PTGIR and TBXA2R promoters was positively correlated with recurrence in oropharyngeal cancer (P = 0.028 and P = 0.006, respectively). Moreover, Patients with 5-9 methylated genes were extremely lower of 5hmC levels (P = 0.035) and was correlated with increasing expression of DNMT3A and DNMT3B (P < 0.05 and P < 0.05, respectively).ConclusionWe characterised the relationship between the methylation status of prostanoid receptor genes and recurrence in HNSCC. These results provide new perspectives for the development of molecular targeted treatment approaches.

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

Publications

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

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