Browsing by Subject "single-nucleotide polymorphism"
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Item Open Access Association of genetic variants of FBXO32 and FOXO6 in the FOXO pathway with breast cancer risk.(Molecular carcinogenesis, 2021-07) Wang, Haijiao; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Akinyemiju, Tomi; Hwang, Shelley; Yue, Ying; Wei, QingyiForkhead box class O (FOXO) transcription factors play a pivotal role in regulating a variety of biological processes, including organismal development, cell signaling, cell metabolism, and tumorigenesis. Therefore, we hypothesize that genetic variants in FOXO pathway genes are associated with breast cancer (BC) risk. To test this hypothesis, we conducted a large meta-analysis using 14 published genome-wide association study (GWAS) data sets in the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study. We assessed associations between 5214 (365 genotyped in DRIVE and 4849 imputed) common single-nucleotide polymorphisms (SNPs) in 55 FOXO pathway genes and BC risk. After multiple comparison corrections by the Bayesian false-discovery probability method, we found five SNPs to be significantly associated with BC risk. In stepwise multivariate logistic regression analysis with adjustment for age, principal components, and previously published SNPs in the same data set, three independent SNPs (i.e., FBXO32 rs10093411 A>G, FOXO6 rs61229336 C>T, and FBXO32 rs62521280 C>T) remained to be significantly associated with BC risk (p = 0.0008, 0.0011, and 0.0017, respectively). Additional expression quantitative trait loci analysis revealed that the FBXO32 rs62521280 T allele was associated with decreased messenger RNA (mRNA) expression levels in breast tissue, while the FOXO6 rs61229336 T allele was found to be associated with decreased mRNA expression levels in the whole blood cells. Once replicated by other investigators, these genetic variants may serve as new biomarkers for BC risk.Item Open Access Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.(Cancer medicine, 2020-11-16) Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Moorman, Patricia G; Walsh, Kyle M; Li, Wei; Wei, QingyiBecause the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.Item Open Access Genetic variants in ELOVL2 and HSD17B12 predict melanoma-specific survival.(International journal of cancer, 2019-02-08) Dai, Wei; Liu, Hongliang; Xu, Xinyuan; Ge, Jie; Luo, Sheng; Zhu, Dakai; Amos, Christopher I; Fang, Shenying; Lee, Jeffrey E; Li, Xin; Nan, Hongmei; Li, Chunying; Wei, QingyiFatty acids play a key role in cellular bioenergetics, membrane biosynthesis and intracellular signaling processes and thus may be involved in cancer development and progression. In the present study, we comprehensively assessed associations of 14,522 common single-nucleotide polymorphisms (SNPs) in 149 genes of the fatty-acid synthesis pathway with cutaneous melanoma disease-specific survival (CMSS). The dataset of 858 cutaneous melanoma (CM) patients from a published genome-wide association study (GWAS) by The University of Texas M.D. Anderson Cancer Center was used as the discovery dataset, and the identified significant SNPs were validated by a dataset of 409 CM patients from another GWAS from the Nurses' Health and Health Professionals Follow-up Studies. We found 40 noteworthy SNPs to be associated with CMSS in both discovery and validation datasets after multiple comparison correction by the false positive report probability method, because more than 85% of the SNPs were imputed. By performing functional prediction, linkage disequilibrium analysis, and stepwise Cox regression selection, we identified two independent SNPs of ELOVL2 rs3734398 T>C and HSD17B12 rs11037684 A>G that predicted CMSS, with an allelic hazards ratio of 0.66 (95% confidence interval = 0.51-0.84 and p = 8.34 × 10-4 ) and 2.29 (1.55-3.39 and p = 3.61 × 10-5 ), respectively. Finally, the ELOVL2 rs3734398 variant CC genotype was found to be associated with a significantly increased mRNA expression level. These SNPs may be potential markers for CM prognosis, if validated by additional larger and mechanistic studies.Item Open Access Genetic variants in PDSS1 and SLC16A6 of the ketone body metabolic pathway predict cutaneous melanoma-specific survival.(Molecular carcinogenesis, 2020-06) Dai, Wei; Liu, Hongliang; Chen, Ka; Xu, Xinyuan; Qian, Danwen; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Li, Xin; Nan, Hongmei; Li, Chunying; Wei, QingyiA few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival through genome-wide association studies, but stringent multiple testing corrections required for the hypothesis-free testing may have masked some true associations. Using a hypothesis-driven analysis approach, we sought to evaluate associations between SNPs in ketone body metabolic pathway genes and CM survival. We comprehensively assessed associations between 4196 (538 genotyped and 3658 imputed) common SNPs in 44 ketone body metabolic pathway genes and CM survival, using a dataset of 858 patients of a case-control study from The University of Texas M.D. Anderson Cancer Center as the discovery set and another dataset of 409 patients from the Nurses' Health Study and the Health Professionals Follow-up Study as the replication set. There were 95/858 (11.1%) and 48/409 (11.7%) patients who died of CM, respectively. We identified two independent SNPs (ie, PDSS1 rs12254548 G>C and SLC16A6 rs71387392 G>A) that were associated with CM survival, with allelic hazards ratios of 0.58 (95% confidence interval [CI] = 0.44-0.76, P = 9.00 × 10-5 ) and 1.98 (95% CI = 1.34-2.94, P = 6.30 × 10-4 ), respectively. Additionally, associations between genotypes of the SNPs and messenger RNA expression levels of their corresponding genes support the biologic plausibility of a role for these two variants in CM tumor progression and survival. Once validated by other larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be valuable biomarkers for CM survival.Item Open Access Genetic variants in the folate metabolic pathway genes predict melanoma-specific survival.(The British journal of dermatology, 2020-01-18) Dai, W; Liu, H; Liu, Y; Xu, X; Qian, D; Luo, S; Cho, E; Zhu, D; Amos, CI; Fang, S; Lee, JE; Li, X; Nan, H; Li, C; Wei, QBACKGROUND:Folate metabolism plays an important role in DNA methylation and nucleic acid synthesis and thus may function as a regulatory factor in cancer development. Genome-wide association studies (GWAS) have identified some single-nucleotide polymorphisms (SNPs) associated with cutaneous melanoma-specific survival (CMSS), but no SNPs were found in genes involved in the folate metabolic pathway. OBJECTIVE:To examine associations between SNPs in folate metabolic pathway genes and CMSS. METHODS:We comprehensively evaluated 2,645 (422 genotyped and 2,223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas M.D. Anderson Cancer Center and performed the validation in another GWAS of 409 patients from the Nurses' Health Study and Health Professionals Follow-up Study, in which 95/858 (11.1%) and 48/409 (11.5%) patients died of cutaneous melanoma, respectively. RESULTS:We identified two independent SNPs (MTHFD1 rs1950902 G>A and ALPL rs10917006 C>T) to be associated with CMSS in both datasets, and their meta-analysis yielded an allelic hazards ratio of 1.75 (95% confidence interval=1.32-2.32, P=9.96×10-5 ) and 2.05 (1.39-3.01, P=2.84×10-4 ), respectively. The genotype-phenotype correlation analyses provided additional support for biologic plausibility of these two variants' roles in tumour progression, suggesting that variation in SNP-related mRNA expression levels is likely to be the mechanism underlying the observed associations with CMSS. CONCLUSION:Two possibly functional genetic variants, MTHFD1 rs1950902 and ALPL rs10917006, were likely to be independently or jointly associated with CMSS, which may add to personalized treatment in the future, once further validated.Item Open Access Genetic variants of DOCK2, EPHB1 and VAV2 in the natural killer cell-related pathway are associated with non-small cell lung cancer survival.(American journal of cancer research, 2021-01) Du, Hailei; Liu, Lihua; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Du, Mulong; Christiani, David C; Wei, QingyiAlthough natural killer (NK) cells are a known major player in anti-tumor immunity, the effect of genetic variation in NK-associated genes on survival in patients with non-small cell lung cancer (NSCLC) remains unknown. Here, in 1,185 with NSCLC cases of a discovery dataset, we evaluated associations of 28,219 single nucleotide polymorphisms (SNPs) in 276 NK-associated genes with their survival. These patients were from the reported genome-wide association study (GWAS) from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We further validated the findings in an additional 984 cases from the Harvard Lung Cancer Susceptibility (HLCS) Study. We identified three SNPs (i.e., DOCK2 rs261083 G>C, VAV2 rs2519996 C>T and EPHB1 rs36215 A>G) to be independently associated with overall survival (OS) in NSCLC cases with adjusted hazards ratios (HRs) of 1.16 (95% confidence interval [CI] = 1.07-1.26, P = 3.34×10-4), 1.28 (1.12-1.47, P = 4.57×10-4) and 0.75 (0.67-0.83, P = 1.50×10-7), respectively. Additional joint assessment of the unfavorable genotypes of the three SNPs showed significant associations with OS and disease-specific survival of NSCLC cases in the PLCO dataset (P trend<0.0001 and <0.0001, respectively). Moreover, the survival-associated DOCK2 rs261083 C allele had a significant correlation with reduced DOCK2 transcript levels in lung adenocarcinoma (LUAD), while the rs36215 G allele was significantly correlated with reduced EPHB1 transcript levels in lymphoblastoid cell lines in the 1000 Genomes Project. These results revealed that DOCK2 and EPHB1 genetic variants may be prognostic biomarkers of NSCLC survival, likely via transcription regulation of respective genes.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 Genetic variants of CHEK1, PRIM2 and CDK6 in the mitotic phase-related pathway are associated with nonsmall cell lung cancer survival.(International journal of cancer, 2021-05-31) Mu, Rui; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Du, Mulong; Christiani, David C; Jin, Lei; Wei, QingyiThe mitotic phase is a vital step in cell division and may be involved in cancer progression, but it remains unclear whether genetic variants in mitotic phase-related pathways genes impact the survival of these patients. Here, we investigated associations between 31 032 single nucleotide polymorphisms (SNPs) in 368 mitotic phase-related pathway genes and overall survival (OS) of patients with nonsmall cell lung cancer (NSCLC). We assessed the associations in a discovery data set of 1185 NSCLC patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another data set of 984 patients from the Harvard Lung Cancer Susceptibility Study. As a result, we identified three independent SNPs (ie, CHEK1 rs76744140 T>C, PRIM2 rs6939623 G>T and CDK6 rs113181986 G>C) to be significantly associated with NSCLC OS with an adjusted hazard ratio of 1.29 (95% confidence interval = 1.11-1.49, P = 8.26 × 10-4 ), 1.26 (1.12-1.42, 1.10 × 10-4 ) and 0.73 (0.63-0.86, 1.63 × 10-4 ), respectively. Moreover, the number of combined unfavorable genotypes of these three SNPs was significantly associated with NSCLC OS and disease-specific survival in the PLCO data set (Ptrend < .0001 and .0003, respectively). Further expression quantitative trait loci analysis showed that the rs76744140C allele predicted CHEK1 mRNA expression levels in normal lung tissues and that rs113181986C allele predicted CDK6 mRNA expression levels in whole blood tissues. Additional analyses indicated CHEK1, PRIM2 and CDK6 may impact NSCLC survival. Taken together, these findings suggested that these genetic variants may be prognostic biomarkers of patients with NSCLC.Item Open Access Genetic Variants of CLEC4E and BIRC3 in Damage-Associated Molecular Patterns-Related Pathway Genes Predict Non-Small Cell Lung Cancer Survival.(Front Oncol, 2021) Liu, Lihua; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wei, QingyiAccumulating evidence supports a role of various damage-associated molecular patterns (DAMPs) in progression of lung cancer, but roles of genetic variants of the DAMPs-related pathway genes in lung cancer survival remain unknown. We investigated associations of 18,588 single-nucleotide polymorphisms (SNPs) in 195 DAMPs-related pathway genes with non-small cell lung cancer (NSCLC) survival in a subset of genotyping data for 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another independent subset of genotyping data for 984 patients from Harvard Lung Cancer Susceptibility Study. We performed multivariate Cox proportional hazards regression analysis, followed by expression quantitative trait loci (eQTL) analysis, Kaplan-Meier survival analysis and bioinformatics functional prediction. We identified that two SNPs (i.e., CLEC4E rs10841847 G>A and BIRC3 rs11225211 G>A) were independently associated with NSCLC overall survival, with adjusted allelic hazards ratios of 0.89 (95% confidence interval=0.82-0.95 and P=0.001) and 0.82 (0.73-0.91 and P=0.0003), respectively; so were their combined predictive alleles from discovery and replication datasets (P trend=0.0002 for overall survival). We also found that the CLEC4E rs10841847 A allele was associated with elevated mRNA expression levels in normal lymphoblastoid cells and whole blood cells, while the BIRC3 rs11225211 A allele was associated with increased mRNA expression levels in normal lung tissues. Collectively, these findings indicated that genetic variants of CLEC4E and BIRC3 in the DAMPs-related pathway genes were associated with NSCLC survival, likely by regulating the mRNA expression of the corresponding genes.Item Open Access Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.(Cancer science, 2021-08-10) He, Yuanmin; Liu, Hongliang; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Li, Xin; Nan, Hongmei; Wei, QingyiMitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed mitotic rate as a category criterion of the tumor T-category, based on the evidence that mitotic rate was not an independent prognostic factor for melanoma survival. Since single-nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma-specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis-related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses' Health Study and Health Professionals Follow-up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval=1.17-1.90, P=0.001) and 1.45 (1.13-1.86, P=0.003), respectively. Furthermore, their combined unfavorable alleles also predicted poor survival in both discovery and validation datasets in a dose-response manner (Ptrend =0.0006 and 0.0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis.Item Open Access Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer.(Molecular carcinogenesis, 2020-05-05) Liu, Xiaowen; Qian, Danwen; Liu, Hongliang; Abbruzzese, James L; Luo, Sheng; Walsh, Kyle M; Wei, QingyiBecause the peroxisome proliferator-activated receptor (PPAR) signaling pathway is involved in development and progression of pancreatic cancer, we investigated associations between genetic variants of the PPAR pathway genes and pancreatic cancer risk by using three published genome-wide association study datasets including 8477 cases and 6946 controls of European ancestry. Expression quantitative trait loci (eQTL) analysis was also performed for correlations between genotypes of the identified genetic variants and messenger RNA (mRNA) expression levels of their genes by using available databases of the 1000 Genomes, TCGA, and GTEx projects. In the single-locus logistic regression analysis, we identified 1141 out of 17 532 significant single-nucleotide polymorphisms (SNPs) in 112 PPAR pathway genes. Further multivariate logistic regression analysis identified three independent, potentially functional loci (rs12947620 in MED1, rs11079651 in PRKCA, and rs34367566 in PRKCB) for pancreatic cancer risk (odds ratio [OR] = 1.11, 95% confidence interval [CI], [1.06-1.17], P = 5.46 × 10-5 ; OR = 1.10, 95% CI, [1.04-1.15], P = 1.99 × 10-4 ; and OR = 1.09, 95% CI, [1.04-1.14], P = 3.16 × 10-4 , respectively) among 65 SNPs that passed multiple comparison correction by false discovery rate (< 0.2). When risk genotypes of these three SNPs were combined, carriers with 2 to 3 unfavorable genotypes (NUGs) had a higher risk of pancreatic cancer than those with 0 to 1 NUGs. The eQTL analysis showed that rs34367566 A>AG was associated with decreased expression levels of PRKCB mRNA in 373 lymphoblastoid cell lines. Our findings indicate that genetic variants of the PPAR pathway genes, particularly MED1, PRKCA, and PRKCB, may contribute to susceptibility to pancreatic cancer.Item Open Access Genetics of Neurogenic Orthostatic Hypotension in Parkinson's Disease, Results from a Cross-Sectional In Silico Study.(Brain sciences, 2023-03) Chevalier, Guenson; Udovin, Lucas; Otero-Losada, Matilde; Bordet, Sofia; Capani, Francisco; Luo, Sheng; Goetz, Christopher G; Perez-Lloret, SantiagoThe genetic basis of Neurogenic Orthostatic Hypotension (NOH) in Parkinson's disease (PD) has been inadequately explored. In a cross-sectional study, we examined the association between NOH and PD-related single-nucleotide polymorphisms (SNPs) and mapped their effects on gene expression and metabolic and signaling pathways. Patients with PD, free from pathological conditions associated with OH, and not taking OH-associated medications were included. NOH was defined as per international guidelines. Logistic regression was used to relate SNPs to NOH. Linkage-disequilibrium analysis, expression quantitative trait loci, and enrichment analysis were used to assess the effects on gene expression and metabolic/signaling pathways. We included 304 PD patients in the study, 35 of whom had NOH (11.5%). NOH was more frequent in patients with SNPs in SNCA, TMEM175, FAM47E-STBD1, CCDC62, SCN3A, MIR4696, SH3GL2, and LZTS3/DDRGK1 and less frequent in those with SNPs in ITGA8, IP6K2, SIPA1L2, NDUFAF2. These SNPs affected gene expression associated with the significant hierarchical central structures of the autonomic nervous system. They influenced several metabolic/signaling pathways, most notably IP3/Ca++ signaling, the PKA-CREB pathway, and the metabolism of fatty acids. These findings provide new insights into the pathophysiology of NOH in PD and may provide targets for future therapies.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 Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival.(Cancers, 2020-01-24) Zhou, Bingrong; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Li, Xin; Nan, Hongmei; Wei, QingyiBecause aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients. To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from Harvard University nurse/physician cohorts. In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44-0.83 and p = 0.002) and 0.66 (0.52-0.84 and 0.004), respectively. Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05). Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.Item Open Access Novel genetic variants of PIP5K1C and MVB12B of the endosome-related pathway predict cutaneous melanoma-specific survival.(American journal of cancer research, 2020-01) Lu, Guiqing; Zhou, Bingrong; He, Yuanmin; Liu, Hongliang; Luo, Sheng; Amos, Christopher I; Lee, Jeffrey E; Yang, Keming; Qureshi, Abrar; Han, Jiali; Wei, QingyiEndosomes regulate cell polarity, adhesion, signaling, immunity, and tumor progression, which may influence cancer outcomes. Here we evaluated associations between 36,068 genetic variants of 228 endosome-related pathway genes and cutaneous melanoma disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies. The discovery dataset included 858 CM patients with 95 deaths from The University of Texas MD Anderson Cancer Center, and the replication dataset included 409 CM patients with 48 deaths from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). In multivariate Cox proportional hazards regression analysis, we found that two novel SNPs (PIP5K1C rs11666894 A>C and MVB12B rs12376285 C>T) predicted CMSS, with adjusted hazards ratios of 1.47 (95% confidence interval = 1.15-1.89 and P = 0.002) and 1.73 (1.30-2.31 and 0.0002), respectively. Combined analysis of risk genotypes of these two SNPs revealed a dose-dependent decrease in CMSS associated with an increased number of risk genotypes (P trend = 0.0002). Subsequent expression quantitative trait loci (eQTL) analysis revealed that PIP5K1C rs11666894 was associated with mRNA expression levels in lymphoblastoid cell lines from 373 European descendants (P<0.0001) and that MVB12B rs12376285 was associated with mRNA expression levels in cultured fibroblasts from 605 European-Americans (P<0.0001). Our findings suggest that novel genetic variants of PIP5K1C and MVB12B in the endosome-related pathway genes may be promising prognostic biomarkers for CMSS, but these results need to be validated in future larger studies.Item Open Access Novel genetic variants of SYK and ITGA1 related lymphangiogenesis signaling pathway predict non-small cell lung cancer survival.(American journal of cancer research, 2020-01) Liu, Lihua; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wei, QingyiAlthough lymphangiogenesis is a vital step in lung cancer metastasis, the association between lymphangiogenesis and non-small cell lung cancer (NSCLC) survival remains unclear. Since single-nucleotide polymorphisms (SNPs) have been reported to predict NSCLC survival, we investigated associations between SNPs in lymphangiogenesis-related pathway genes and NSCLC survival in a discovery genotyping dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the findings in another genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility Study. We evaluated associations between 34,509 genetic variants (3252 genotyped and 31,257 imputed) in 247 genes involved in lymphangiogenesis-related pathway and NSCLC survival. After validation, we finally identified two independent SNPs (SYK rs11787670 A>G and ITGA1 rs67715745 T>C) to be significantly associated with NSCLC overall survival (OS), with adjusted hazards ratios of 0.77 and 0.83 (95% confidence interval =0.66-0.90, P=7.20×10-4) and 0.84 (95% confidence interval =0.75-0.92, P=3.50×10-4), respectively. Moreover, an increasing number of combined protective alleles of these two SNPs was significantly associated with an improved NSCLC OS and disease-specific survival (DSS) in the PLCO dataset (P trend=0.011 and 0.006, respectively). Furthermore, the addition of these protective alleles to the prediction model for the 5-year survival increased the time-dependent area under the curve both from 87% to 87.67% for OS (P=0.029) and from 88.54% to 89.06% for DSS (P=0.022). Subsequent expression quantitative trait loci (eQTL) functional analysis revealed that the rs11787670 G allele was significantly associated with an elevated SYK mRNA expression in normal tissues. Additional analyses suggested a suppressor role for both SYK and ITGA1 in NSCLC survival. Collectively, these findings indicated that SYK rs11787670 A>G and ITGA1 rs67715745 T>C may be independent prognostic factors for NSCLC survival once further validated.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 genetic variants in the complement-related immunity gene-set are associated with non-small cell lung cancer survival.(International journal of cancer, 2019-04) Qian, Danwen; Liu, Hongliang; Wang, Xiaomeng; Ge, Jie; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiThe complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody-based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two-phase analysis of two independently published genome-wide association studies (GWASs) for associations between genetic variants in a complement-related immunity gene-set and overall survival of non-small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false-positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single-nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single-locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07-1.40, P = 0.002] and 1.16 (1.07-1.27, 6.45 × 10-4 ), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival-associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement-related immunity genes might be predictors of NSCLC survival, particularly for the short-term survival, possibly by modulating the expression of genes involved in the host immunity.Item Open Access Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial.(Molecular carcinogenesis, 2019-04-15) Guo, Yi; Feng, Yun; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey W; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, QingyiThe tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non-small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively. We selected 6788 SNPs in 71 genes in the TNF/TNFR signaling pathway and extracted their genotyping data from the PLCO genowide-association study (GWAS) dataset. We performed Cox proportional hazards regression analysis to evaluate associations between the identified SNPs and survival and validated the significant SNPs, which were further analyzed for their functional relevance. We found that genotypes of two validated SNPs, IKBKAP rs4978754 CT + TT and TNFRSF1B rs677844 TC + CC, as well as their combined genotypes predicted a better overall survival (P = 0.004, 0.002 and <0.001, respectively). These two validated SNPs were predicted by the RegulomeDB score to be potentially functional. In addition, IKBKAP mRNA expression levels were significantly higher, while TNFRSF1B mRNA expression levels were significantly lower in lung cancer tissues than in adjacent normal tissues (P < 0.001). The Cancer Genome Atlas (TCGA)-based expression quantitative trait loci analysis showed that IKBKAP rs4978754 and TNFRSF1B rs677844 genotypes were significantly associated with their corresponding mRNA expression levels in lung cancer tissues in a recessive model (P = 0.035 and 0.045, respectively). Therefore, we identified two potentially functional SNPs (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with NSCLC.Item Open Access Single nucleotide polymorphisms in FOXP1 and RORA of the lymphocyte activation-related pathway affect survival of lung cancer patients(Translational Lung Cancer Research, 2022-05) Du, Hailei; Mu, Rui; Liu, Lihua; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Glass, Carolyn; Su, Li; Du, Mulong; Christiani, David C; Li, Hecheng; Wei, Qingyi