Browsing by Author "Tang, Dongfang"
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Item Open Access Genetic variants of BIRC3 and NRG1 in the NLRP3 inflammasome pathway are associated with non-small cell lung cancer survival.(American journal of cancer research, 2020-01) Tang, Dongfang; Liu, Hongliang; Zhao, Yuchen; Qian, Danwen; Luo, Sheng; Patz, Edward F; Su, Li; Shen, Sipeng; ChristianI, David C; Gao, Wen; Wei, QingyiThe nod-like receptor protein 3 (NLRP3) is one of the most characterized inflammasomes, and its genetic variation and functional dysregulation are involved in pathogenesis of several cancers. To systematically evaluate the role of NLRP3 in predicting outcomes of patients with non-small cell lung cancer (NSCLC), we performed a two-phase analysis for associations between genetic variants in NLRP3 inflammasome pathway genes and NSCLC survival by using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We used multivariate Cox proportional hazards regression analysis with Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 20,730 single-nucleotide polymorphisms (SNPs) in 176 genes and overall survival of 1,185 NSCLC patients from the PLCO trial. We further validated the identified significant SNPs in another GWAS dataset with survival data from 984 NSCLC patients of the Harvard Lung Cancer Susceptibility (HLCS) study. The results showed that two independent SNPs in two different genes (i.e., BIRC3 rs11225211 and NRG1 rs4733124) were significantly associated with the NSCLC overall survival, with a combined hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.74-0.93 and P = 0.0009] and 1.18 (95% CI = 1.06-1.31) and P = 0.002], respectively. However, further expression quantitative trait loci (eQTL) analysis showed no evidence for correlations between the two SNPs and mRNA expression levels of corresponding genes. These results indicated that genetic variants in the NLRP3 imflammasome pathway gene-sets might be predictors of NSCLC survival, but the molecular mechanisms underlying the observed associations warrant further investigations.Item Open Access Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.(Molecular carcinogenesis, 2019-11-12) Tang, Dongfang; Zhao, Yu Chen; Qian, Danwen; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Glass, Carolyn; Gao, Wen; Wei, QingyiThe CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.Item Open Access Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival.(International journal of cancer, 2019-10-16) Yang, Sen; Tang, Dongfang; Zhao, Yu C; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, QingyiThe endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways. Here, by analyzing two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small cell lung cancer (NSCLC). The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a single locus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility study, 14 SNPs remained significant. The final multivariate stepwise Cox proportional hazards regression model in the PLCO datasets identified three potentially functional and independent SNPs (KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 [95% confidence interval (CI)=0.79-0.94, P=0.0007], 1.31 (1.16-1.47, P=6.0×10-5 ) and 1.27 (1.12-1.44, P=0.0001) for overall survival (OS), respectively. Combined analysis of the adverse genotypes of these three SNPs revealed a trend in the genotype-survival association (Ptrend <0.0001 for OS and Ptrend <0.0001 for disease-specific survival). Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells. Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes. This article is protected by copyright. All rights reserved.Item Open Access Novel variants of ELP2 and PIAS1 in the interferon gamma signaling pathway are associated with non-small cell lung cancer survival.(Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2020-06-03) Zhao, Yu Chen; Tang, Dongfang; Yang, Sen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiBACKGROUND:Interferon gamma (IFNγ) is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses. Despite recognition of IFNγ signaling effects on host defense against viral infection and its utility in immunotherapy and tumor progression, the roles of genetic variants of the IFNγ signaling pathway genes in cancer patient survival remain unknown. METHODS:We used a discovery genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (n=1,185) and a replication genotyping dataset from the Harvard Lung Cancer Susceptibility Study (n=984) to evaluate associations between 14,553 genetic variants in 150 IFNγ pathway genes and survival of non-small cell lung cancer (NSCLC). RESULTS:The combined analysis identified two independent potentially functional single-nucleotide polymorphisms (SNPs), ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 0.85 [95% CI= 0.78-0.92, P<0.0001] and 0.87 (0.81-0.93, P<0.0001), respectively. Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of ELP2 in 373 lymphoblastoid cell lines and 369 whole blood samples. The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole blood samples. CONCLUSIONS:Genetic variants of IFNγ signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response. IMPACT:Once validated, these variants could be useful predictors of NSCLC survival.Item Open Access Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer.(International journal of cancer, 2020-02-18) Tang, Dongfang; Zhao, Yu C; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey M; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Gao, Wen; Wei, QingyiThe ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09-1.36 and p = 0.0003], 0.82 (0.74-0.91 and p = 0.0002) and 1.21 (1.10-1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.Item Open Access Potentially functional variants of ERAP1, PSMF1 and NCF2 in the MHC-I-related pathway predict non-small cell lung cancer survival.(Cancer immunology, immunotherapy : CII, 2021-03-02) Yang, Sen; Tang, Dongfang; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Wang, Qiming; Wei, QingyiBackground
Cellular immunity against tumor cells is highly dependent on antigen presentation by major histocompatibility complex class I (MHC-I) molecules. However, few published studies have investigated associations between functional variants of MHC-I-related genes and clinical outcomes of lung cancer patients.Methods
We performed a two-phase Cox proportional hazards regression analysis by using two previously published genome-wide association studies to evaluate associations between genetic variants in the MHC-I-related gene set and the survival of non-small cell lung cancer (NSCLC) patients, followed by expression quantitative trait loci analysis.Results
Of the 7811 single-nucleotide polymorphisms (SNPs) in 89 genes of 1185 NSCLC patients in the discovery dataset of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, 24 SNPs remained statistically significant after validation in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. In a multivariate stepwise Cox model, three independent functional SNPs (ERAP1 rs469783 T > C, PSMF1 rs13040574 C > A and NCF2 rs36071574 G > A) remained significant with an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) = 0.77-0.89, P = 8.0 × 10-7], 0.86 (0.80-0.93, P = 9.4 × 10-5) and 1.31 (1.11-1.54, P = 0.001) for overall survival (OS), respectively. Further combined genotypes revealed a poor survival in a dose-response manner in association with the number of unfavorable genotypes (Ptrend < 0.0001 and 0.0002 for OS and disease-specific survival, respectively). Also, ERAP1 rs469783C and PSMF1 rs13040574A alleles were associated with higher mRNA expression levels of their genes.Conclusion
These potentially functional SNPs of the MHC-I-related genes may be biomarkers for NSCLC survival, possibly through modulating the expression of corresponding genes.Item Open Access Potentially functional variants of HBEGF and ITPR3 in GnRH signaling pathway genes predict survival of non-small cell lung cancer patients.(Translational research : the journal of laboratory and clinical medicine, 2021-01-02) Wu, Yufeng; Liu, Zhensheng; Tang, Dongfang; Liu, Hongliang; Luo, Sheng; Stinchcombe, Thomas E; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wang, Qiming; Wei, QingyiThe gonadotropin-releasing hormone (GnRH) signaling pathway controls reproductive functions and cancer growth and progression. However, few studies investigated roles of genetic variants of GnRH pathway genes in survival of patients with non-small cell lung cancer (NSCLC). Therefore, we first evaluated associations between 22,528 single-nucleotide polymorphisms (SNPs) in 101 GnRH pathway genes and survival of 1185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We found 572 SNPs to be significantly associated with overall survival (OS) of NSCLC (P ≤ 0.05, Bayesian false discovery probability ≤0.80). We then validated these SNPs in another dataset with 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS in the combined analysis with hazards ratios of 0.84 (95% confidence interval = 0.76-0.92, P = 0.0003) and 0.85 (0.78-0.94, 0.0012), respectively; their genetic score (the number of protective genotypes) was associated with a better OS and disease-specific survival (Ptrend = 0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed a significant correlation between ITPR3 rs116454384 T allele and an increased mRNA expression level in both whole blood and normal lung tissue, and high ITPR3 mRNA expression levels in tumors were associated with a better survival of NSCLC patients. Because ITPR3 mutations were rare in tumors, ITPR3 rs116454384C>T likely had an effect on cancer progression by regulating the gene expression. Therefore, genetic variants of HBEGF rs4150236G>A and ITPR3 rs116454384C>T may be predictors for NSCLC survival, but HBEGF rs4150236G>A functional relevance remains to be determined.