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Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma.

ABSTRACT: Curatively treated patients with early-stage head and neck squamous cell carcinoma (HNSCC) are at high risks for second primary tumor (SPT) and recurrence. The regulator of G-protein signaling (RGS) is important in essential signaling transduction and cellular activities. We hypothesize that genetic variations of RGS may modulate the risk of SPT/recurrence in patients with early-stage HNSCC. In a nested case-control study, we evaluated 98 single-nucleotide polymorphisms (SNPs) in 17 RGS genes for the risk of SPT/recurrence among 450 HNSCC patients. Eight SNPs showed significant associations with the risk of SPT/recurrence, with the most significant one of rs2179653, which is located in the 5'-flanking region of RGS2 gene. Under a recessive genetic model, the homozygous variant genotype of this SNP was associated with 2.95-fold [95% confidence interval (CI): 1.52-5.74] increased risk of SPT/recurrence. This association remained significant after the adjustment for multiple comparisons. Cumulative effects analysis revealed that the risk increased significantly with the increasing numbers of unfavorable genotypes. Compared with subjects carrying 0-2 unfavorable genotypes, the hazard ratios (95% CIs) for those carrying 3 or 4+ were 1.73 (1.10-2.70) and 3.05 (1.92-4.83), respectively. Furthermore, survival tree analysis revealed potential higher order gene-gene interactions and indicated different outcomes based on distinct genotype profiles. Genetic variations of RGS genes may modulate the susceptibility to SPT/recurrence in early-stage HNSCC patients individually and cumulatively. Our results stressed the importance of taking a polygenic approach to evaluate the cumulative and interaction effects of genetic variations in the prediction of cancer risk and prognosis.

SUBMITTER: Wang J

PROVIDER: S-EPMC2950933 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:ImportanceSecond primary malignant neoplasms (SPMNs) are the leading cause of death in survivors of head and neck squamous cell carcinoma (HNSCC). Recently, human papillomavirus (HPV) has emerged as a risk factor for oropharyngeal squamous cell carcinoma and has different prognosis from classic tobacco/alcohol-associated HNSCC. This suggests that there also may be different risks and burden of SPMNs among patients who's HNSCC were from HPV or tobacco and/or alcohol.ObjectiveTo assess SPMN risks and burden in a large US cohort of patients with a first potentially HPV-associated HNSCC vs non-HPV-associated HNSCC.Design, setting, and participantsIn this population-based retrospective cohort study, 109 512 adult patients diagnosed with HNSCC between 2000 and 2014 were identified from the Surveillance, Epidemiology, and End Results registry.ExposuresHPV-relatedness based on whether patients' first HNSCC was potentially associated with HPV. Patients were grouped into 2 cohorts: potentially HPV-associated HNSCC, and non-HPV-associated HNSCC.Main outcomes and measuresThe primary outcome was incidence of SPMN (defined as the first subsequent primary cancer occurring at least 2 months after first cancer diagnosis). Excess SPMN risk was calculated using relative (standardized incidence ratios [SIRs]) and absolute (excess absolute risk [EAR] per 10 000 person-years at risk [PYR]).ResultsA total of 109 512 patients with HNSCC (mean [SD] age, 61.9 [12.1] years; 83 305 [76.1%] men) were identified. The overall SIR was 2.18 (95% CI, 2.14-2.22) corresponding to 160 excess cases per 10 000 PYR. The risk among patients with first potentially HPV-associated HNSCC (SIR, 1.98; EAR, 114 excess cases per 10 000 PYR) was lower than those with first non-HPV-associated HNSCC (SIR, 2.28; EAR, 188 excess cases per 10 000 PYR). Overall, the largest SIRs and EARs were observed for cancers of the head and neck, lung, and esophagus. However, the risks of SPMN were lower among potentially HPV-associated HNSCC patients.Conclusions and relevancePatients diagnosed with HNSCC experience excess risk of SPMN, which was higher among those with non-HPV-associated HNSCC than from potentially HPV-associated HNSCC. Clinicians should implement strategies that prevent or detect SPMN early in patients with HNSCC.

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Genetic variations in regulator of G-protein signaling genes as susceptibility loci for second primary tumor/recurrence in head and neck squamous cell carcinoma.

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