Browsing by Subject "Oropharyngeal Neoplasms"
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Item Open Access A functional variant at miRNA-122 binding site in IL-1a 3' UTR predicts risk of recurrence in patients with oropharyngeal cancer.(Oncotarget, 2016-06) Wang, Chengyuan; Sturgis, Erich M; Chen, Xingming; Wei, Qingyi; Li, GuojunIL-1a, an important regulator of immune and inflammation responses, has been implicated in cancer development and prognosis. An insertion (Ins)/deletion (Del) polymorphism (IL-1a rs3783553) in the 3' UTR of IL-1a may disrupt a binding site for miRNA-122 and may affect its transcription level. Thus, this polymorphism may cause interindividual variation in immune and inflammation responses and thus may lead to different susceptibility to treatment response and prognosis of such patients. We evaluated the association of IL-1a rs3783553 polymorphism with risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP) in a cohort of 1008 patients. Log-rank test and univariate and multivariable Cox models were used to evaluate associations. Compared with patients with Del/Del homozygous genotype, the patients with Ins/Del+Ins/Ins variant genotypes had worse disease-free survival (log-rank P < 0.0001) and increased risk of SCCOP recurrence (HR, 2.4, 95% CI, 1.7-3.3) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, the patients with Ins/Del+Ins/Ins variant genotypes of the IL-1a polymorphism had worse disease-free survival (log-rank P < 0.0001) and much higher recurrence risk than those with Del/Del homozygous genotype of this polymorphism (HR, 16.3, 95% CI, 5.0-52.7). Our findings suggest that IL-1a rs3783553 polymorphism may modulate the risk of SCCOP recurrence in patients, particularly for patients with HPV16-positive tumors. However, larger studies are needed to validate these results.Item Open Access A TGF-β1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16-associated oropharyngeal cancer.(International journal of cancer, 2018-09) Tao, Ye; Sturgis, Erich M; Huang, Zhigang; Sun, Yan; Dahlstrom, Kristina R; Wei, Qingyi; Li, GuojunTGF-β1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-β1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF-β1rs1982073 polymorphism at the miRNA-187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF-β1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer-free controls in the non-Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF-β1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6-960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2-1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3-87.0 vs. OR, 6.0; 95% CI, 1.7-17.9, respectively). The significant associations between this polymorphism and HPV16-associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF-β1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16-associated oral cancer, particularly in OPSCC subjects who are never-smokers, never-drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.Item Open Access Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.(Int J Cancer, 2015-11-15) Zhang, Fenghua; Sturgis, Erich M; Sun, Yan; Zhang, Yang; Wei, Qingyi; Zhang, Caiyun; Zheng, Hongliang; Li, GuojunSingle nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.Item Open Access Association of combined p73 and p53 genetic variants with tumor HPV16-positive oropharyngeal cancer.(PloS one, 2012-01) Wang, Zhongqiu; Sturgis, Erich M; Guo, Wei; Song, Xicheng; Zhang, Fenghua; Xu, Li; Wei, Qingyi; Li, Guojunp53 and p73 interact with human papillomavirus (HPV) E6 and E7 oncoproteins. The interplay between p53 and p73 and HPV16 may lead to deregulation of cell cycle and apoptosis, through which inflammation/immune responses control the HPV clearance and escape of immune surveillance, and subsequently contribute to tumor HPV16 status. In this case-case comparison study, HPV16 status in tumor specimens was analyzed and p53 codon 72 and p73 G4C14-to-A4T14 polymorphisms were genotyped using genomic DNA from blood of 309 oropharyngeal cancer patients. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated in univariate and multivariable logistic regression models to examine the association. The results from this study showed both p53 variant genotypes (Arg/Pro+Pro/Pro) and p73 variant genotypes (GC/AT+AT/AT) were significantly associated with HPV16-positive tumor in oropharyngeal cancer patients (OR, 1.9, 95% CI, 1.1-3.3 and OR, 2.1, 95% CI, 1.2-3.8, respectively), while the combined variant genotypes (p53 Pro carriers and p73 AT carriers) exhibited a significantly greater association with HPV16-positive tumor (OR, 3.2, 95% CI, 1.4-7.4), compared with combined wild-type genotypes (p53 Arg/Arg and p73 GC/GC), and the association was in a statistically significant dose-effect relationship (p = 0.001). Moreover, such association was more pronounced among several subgroups. These findings suggest that variant genotypes of p53 and p73 genes may be individually, or more likely jointly, associated with tumor HPV16-positive oropharyngeal cancer patients, particularly in never smokers. Identification of such susceptible biomarkers would greatly influence on individualized treatment for an improved prognosis.Item Open Access Early 18F-FDG-PET Response During Radiation Therapy for HPV-Related Oropharyngeal Cancer May Predict Disease Recurrence.(International journal of radiation oncology, biology, physics, 2020-11) Mowery, Yvonne M; Vergalasova, Irina; Rushing, Christel N; Choudhury, Kingshuk Roy; Niedzwiecki, Donna; Wu, Qiuwen; Yoo, David S; Das, Shiva; Wong, Terence Z; Brizel, David MPurpose
Early indication of treatment outcome may guide therapeutic de-escalation strategies in patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC). This study investigated the relationships between tumor volume and 18F-fluorodeoxyglucose positron emission tomography (PET) parameters before and during definitive radiation therapy with treatment outcomes.Methods and materials
Patients undergoing definitive (chemo)radiation for HPV-related/p16-positive OPC were prospectively enrolled on an institutional review board-approved study. 18F-fluorodeoxyglucose PET/computed tomography scans were performed at simulation and after 2 weeks at a dose of ∼20 Gy. Tumor volume and standardized uptake value (SUV) characteristics were measured. SUV was normalized to blood pool uptake. Tumor volume and PET parameters associated with recurrence were identified through recursive partitioning (RPART). Recurrence-free survival (RFS) and overall survival (OS) curves between RPART-identified cohorts were estimated using the Kaplan-Meier method, and Cox models were used to estimate the hazard ratios (HRs).Results
From 2012 to 2016, 62 patients with HPV-related OPC were enrolled. Median follow-up was 4.4 years. RPART identified patients with intratreatment SUVmax (normalized to blood pool SUVmean) <6.7 or SUVmax (normalized to blood pool SUVmean) ≥6.7 with intratreatment SUV40% ≥2.75 as less likely to recur. For identified subgroups, results of Cox models showed unadjusted HRs for RFS and OS (more likely to recur vs less likely) of 7.33 (90% confidence interval [CI], 2.97-18.12) and 6.09 (90% CI, 2.22-16.71), respectively, and adjusted HRs of 6.57 (90% CI, 2.53-17.05) and 5.61 (90% CI, 1.90-16.54) for RFS and OS, respectively.Conclusions
PET parameters after 2 weeks of definitive radiation therapy for HPV-related OPC are associated with RFS and OS, thus potentially informing an adaptive treatment approach.Item Open Access HPV16 antibodies as risk factors for oropharyngeal cancer and their association with tumor HPV and smoking status.(Oral Oncol, 2015-07) Anderson, Karen S; Dahlstrom, Kristina R; Cheng, Julia N; Alam, Rizwan; Li, Guojun; Wei, Qingyi; Gross, Neil D; Chowell, Diego; Posner, Marshall; Sturgis, Erich MBACKGROUND: Antibodies (Abs) to the HPV16 proteome increase risk for HPV-associated OPC (HPVOPC). The goal of this study was to investigate the association of a panel of HPV16 Abs with risk for OPC as well as the association of these Abs with tumor HPV and smoking status among patients with OPC. METHODS: IgG Abs to the HPV16 antigens E1, E2, E4, E5, E6, E7, L1, L2 were quantified using a programmable ELISA assay. Sera were obtained from 258 OPC patients at diagnosis and 250 healthy controls. HPV16 tumor status was measured by PCR for 137 cases. Multivariable logistic regression was used to calculate odds ratios for the association of HPV16 Abs with risk for OPC. RESULTS: HPV16 E1, E2, E4, E5, E6, E7 and L1-specific IgG levels were elevated in OPC patients compared to healthy controls (p<0.05). After multivariable adjustment, Ab positivity for NE2, CE2, E6, and/or E7 was associated with OPC risk (OR [95% CI], 249.1 [99.3-624.9]). Among patients with OPC, Ab positivity for these antigens was associated with tumor HPV status, especially among never or light smokers (OR [95% CI], 6.5 [2.1-20.1] and OR [95% CI], 17.5 [4.0-77.2], respectively). CONCLUSIONS: Antibodies to HPV16 proteins are associated with increased risk for HPVOPC. Among patients with OPC, HPV16 Abs are associated with tumor HPV status, in particular among HPV positive patients with no or little smoking history.Item Open Access MicroRNA variants increase the risk of HPV-associated squamous cell carcinoma of the oropharynx in never smokers.(PloS one, 2013-01) Song, Xicheng; Sturgis, Erich M; Liu, Jun; Jin, Lei; Wang, Zhongqiu; Zhang, Caiyun; Wei, Qingyi; Li, GuojunBoth microRNAs and human papillomavirus (HPV) infection play an important role in the development and progression of oral squamous cell carcinoma (OSCC). In addition, microRNAs affect all facets of the immune/inflammation responses to infection, which may control HPV clearance. We thus hypothesized that microRNA polymorphisms modify the association between HPV16 seropositivity and OSCC risk.Four single-nucleotide polymorphisms in microRNAs were genotyped and HPV16 serology was determined in 325 cases and 335 matched controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using univariate and multivariable logistic regression models.Overall, each polymorphism had no significant main effect on OSCC risk. Compared with the risk among individuals with both miR146 rs2910164 GG genotype and HPV16 seronegativity, risk of OSCC was increased among those with CG or CC genotype and HPV16 seronegativity (OR, 1.2; 95% CI, 0.9-1.8), GG genotype and HPV16 seropositivity (OR, 3.0; 95% CI, 1.8-5.0), and CG or CC genotype and HPV16 seropositivity (OR, 4.7; 95% CI, 2.3-9.4). Similar results were found for miR149 rs2292832, miR196 rs11614913, and miR499 rs3746444. Analyses stratified by tumor sites and smoking status showed that each polymorphism significantly increased the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly prominent in never smokers.Our results indicate that microRNA polymorphisms modify the risk of OSCC associated with HPV16 seropositivity, particularly in patients with SCCOP and never smokers. Larger studies are needed to verify our findings.Item Open Access Modifying effect of mouse double minute-2 promoter variants on risk of recurrence for patients with squamous cell carcinoma of oropharynx.(Scientific reports, 2017-01-03) Zhang, Yang; Sturgis, Erich M; Li, Yuncheng; Wei, Qingyi; Huang, Zhigang; Li, GuojunFunctional mouse double minute-2 (MDM2) promoter variants may alter MDM2 expression and thus affect radiotherapy response and prognosis of squamous cell carcinoma of oropharynx (SCCOP). Thus we assessed association of 2 functional MDM2 promoter variants with recurrence risk of SCCOP. The disease-free survival (DFS) of patients with MDM2rs2279744 TT or MDM2rs937283 AA genotypes was significantly reduced compared with that of patients with corresponding GT/GG or AG/GG genotypes. Multivariable analysis showed patients with TT or AA genotypes had a significantly higher risk of SCCOP recurrence than those with corresponding GT/GG or AG/GG genotypes did. Furthermore, patients with combined risk genotypes of the 2 polymorphisms had significantly worse DFS and a higher recurrence risk than patients with fewer combined risk genotypes did (Ptrend < 0.001). Compared with patients with 0 risk genotypes, patients with 1 or 2 risk genotypes had an approximately 3- or 11-fold increased risk of SCCOP recurrence, respectively. Notably, for both individual and combined polymorphisms, the above similar recurrence risks were particularly higher among patients with human papilloma virus (HPV)-positive tumors. Taken together, our findings suggest that MDM2 promoter variants individually, or more likely jointly, play a role in determining the risk of recurrence of SCCOP, particularly HPV-positive SCCOP.Item Open Access Mouse double minute 4 variants modify susceptibility to risk of recurrence in patients with squamous cell carcinoma of the oropharynx.(Molecular carcinogenesis, 2018-03) Lu, Zhongming; Lu, Zhongming; Sturgis, Erich M; Zhu, Lijun; Zhang, Hua; Tao, Ye; Wei, Peng; Wei, Qingyi; Li, GuojunGiven 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.Item Open Access Pitfalls of post-treatment PET after de-intensified chemoradiotherapy for HPV-associated oropharynx cancer: Secondary analysis of a phase 2 trial.(Oral oncology, 2018-03) Wang, Kyle; Wong, Terence Z; Amdur, Robert J; Mendenhall, William M; Sheets, Nathan C; Green, Rebecca; Thorp, Brian D; Patel, Samip N; Hackman, Trevor G; Zanation, Adam M; Weissler, Mark C; Chera, Bhishamjit SOBJECTIVES:We evaluated patterns of nodal response and positive predictive value (PPV) of 3 month post-treatment PET in patients with HPV-associated oropharyngeal cancer treated on a multi-institutional de-intensification trial. MATERIALS AND METHODS:Eligibility criteria included: (1) T0-3, N0-2c, M0, (2) HPV+/p16+ oropharyngeal squamous cell carcinoma, and (3) ≤10 pack-years smoking or ≤30 pack-years and abstinent ≥5 years. Patients received 60 Gy radiation alone (T0-2, N0-1) or with concurrent weekly cisplatin 30 mg/m2 and surveillance PET three months post-radiation. Nodal responses were categorized as complete (CR), equivocal (ER), or incomplete (IR) using both local and central radiographic review. A "true positive" was ER/IR with clinical/radiographic progression or positive pathology. RESULTS:79 node-positive pts (84% N2) were analyzed. Distribution of nodal CR, ER, and IR was 44 (56%), 27 (34%), and 8 (10%), respectively. 29 (37%) had ER/IR in pre-treatment node-positive neck levels, whereas 14 (18%) had ER/IR in pre-treatment node-negative levels. Of patients with ER/IR, 5 were observed clinically, 19 received repeat imaging, and 11 received either biopsy (1) or neck dissection (10). The PPV was 9% for ER/IR and 13% for IR, with 3 patients found to have persistent disease on neck dissection. There was no difference in nodal relapse rate in patients with nodal CR vs. nodal ER/IR. CONCLUSION:Post-treatment PET may not accurately predict the presence of persistent disease in patients with favorable-risk oropharynx cancer. These results support close surveillance rather than surgical evaluation in most favorable-risk patients.Item Open Access Significance of microRNA-related variants in susceptibility to recurrence of oropharyngeal cancer patients after definitive radiotherapy.(Oncotarget, 2016-06) Chen, Xingming; Sturgis, Erich M; Wang, Chengyuan; Cao, Xiaoli; Li, Yuncheng; Wei, Qingyi; Li, GuojunCommon single nucleotide polymorphisms (SNPs) in miRNAs may affect miRNA functions and their target expression and thus may affect biological activities and cancer etiology as well as prognosis. Thus, we determined whether the 9 SNPs in microRNAs modify the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP) in a cohort of 1008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. We found that the SNPs in the miRNA146, miRNA196, and Gemin3 were associated with a significantly reduced and increased risk of SCCOP recurrence after multivariate adjustment (aHR, 0.6, 95%CI, 0.4-0.9, aHR, 2.1, 95%CI, 1.6-2.8, and aHR, 0.6, 95%CI, 0.5-0.9, respectively). Furthermore, the similar effect of these 3 SNPs on SCCOP recurrence risk was found in HPV-positive SCCOP patients only. However, no significant associations were found for other SNPs. To evaluate the aggregate effects of these SNPs, we performed a combined risk genotype analysis. We found that, compared with the low-risk reference group with less than 4 risk genotypes, the medium-risk group with 4 or 5 risk genotypes exhibited a 1.7-fold (1.2-2.4) increased risk whereas the high-risk group with more than 5 risk genotypes exhibited a 3.0-fold (1.7-4.2) increased risk (Ptrend < 0.001). Such combined effects were particularly pronounced in HPV-positive SCCOP patients. Taken together, this is the first study with a large cohort of SCCOP patients showing that miRNA-related genetic variants may modify risk of SCCOP recurrence individually and jointly. Larger studies are needed to validate these results.