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Browsing by Author "Luo, Sheng"
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Item Association of genetic variants of TMEM135 and PEX5 in the peroxisome pathway with cutaneous melanoma-specific survival(AME Publishing, 2021-03) Wang, Haijiao; Liu, Hongliang; Dai, Wei; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Yue, Ying; Nan, Hongmei; Wei, Qingyi; Epidemiology, School of Public HealthBackground: Peroxisomes are ubiquitous and dynamic organelles that are involved in the metabolism of reactive oxygen species (ROS) and lipids. However, whether genetic variants in the peroxisome pathway genes are associated with survival in patients with melanoma has not been established. Therefore, our aim was to identify additional genetic variants in the peroxisome pathway that may provide new prognostic biomarkers for cutaneous melanoma (CM). Methods: We assessed the associations between 8,397 common single-nucleotide polymorphisms (SNPs) in 88 peroxisome pathway genes and CM disease-specific survival (CMSS) in a two-stage analysis. For the discovery, we extracted the data from a published genome-wide association study from The University of Texas MD Anderson Cancer Center (MDACC). We then replicated the results in another dataset from the Nurse Health Study (NHS)/Health Professionals Follow-up Study (HPFS). Results: Overall, 95 (11.1%) patients in the MDACC dataset and 48 (11.7%) patients in the NHS/HPFS dataset died of CM. We found 27 significant SNPs in the peroxisome pathway genes to be associated with CMSS in both datasets after multiple comparison correction using the Bayesian false-discovery probability method. In stepwise Cox proportional hazards regression analysis, with adjustment for other covariates and previously published SNPs in the MDACC dataset, we identified 2 independent SNPs (TMEM135 rs567403 C>G and PEX5 rs7969508 A>G) that predicted CMSS (P=0.003 and 0.031, respectively, in an additive genetic model). The expression quantitative trait loci analysis further revealed that the TMEM135 rs567403 GG and PEX5 rs7969508 GG genotypes were associated with increased and decreased levels of mRNA expression of their genes, respectively. Conclusions: Once our findings are replicated by other investigators, these genetic variants may serve as novel biomarkers for the prediction of survival in patients with CM.Item Genetic variants in ELOVL2 and HSD17B12 predict melanoma‐specific survival(Wiley, 2019) Dai, Wei; Liu, Hongliang; Xu, Xinyuan; Jie, Ge; Luo, Sheng; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Li, Chunying; Wei, Qingyi; Epidemiology, School of Public HealthFatty 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 Genetic variants in PDSS1 and SLC16A6 of the ketone body metabolic pathway predict cutaneous melanoma-specific survival(Wiley, 2020-03-31) 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, Qingyi; Epidemiology, School of Public HealthA few single-nucleotide polymorphisms (SNPs) have been identified to be associated with cutaneous melanoma (CM) survival though 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 4,196 (538 genotyped and 3,658 imputed) common SNPs in 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 (11.5%) patients who died of CM, respectively. We identified two independent SNPs (i.e., 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 mRNA 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 larger studies, PDSS1 rs12254548 and SLC16A6 rs71387392 may be biomarker for CM survival.Item Genetic variants in TKT and DERA in the NADPH pathway predict melanoma survival(Elsevier, 2020-09) Gu, Ning; Dai, Wei; Liu, Hongliang; Ge, Jie; Luo, Sheng; Cho, Eunyoung; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Yuan, Hua; Wei, Qingyi; Epidemiology, School of Public HealthBackground: Cutaneous melanoma (CM) is the most lethal type of skin cancers. Nicotinamide adenine dinucleotide phosphate (NADPH) plays an important role in anabolic reactions and tumorigenesis, but many genes are involved in the NADPH system. Methods: We used 10,912 single-nucleotide polymorphisms (SNPs) (2018 genotyped and 8894 imputed) in 134 NADPH-related genes from a genome-wide association study (GWAS) of 858 patients from The University of Texas MD Anderson Cancer Center (MDACC) in a single-locus analysis to predict CM survival. We then replicated the results in another GWAS data set of 409 patients from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Results: There were 95 of 858 (11.1%) and 48 of 409 (11.7%) patients who died of CM, respectively. In multivariable Cox regression analyses, we identified two independent SNPs (TKT rs9864057 G > A and deoxyribose phosphate aldolase (DERA) rs12297652 A > G) to be significantly associated with CM-specific survival [hazards ratio (HR) of 1.52, 95% confidence interval (CI) = 1.18-1.96, P = 1.06 × 10-3 and 1.51 (1.19-1.91, 5.89 × 10-4)] in the meta-analysis, respectively. Furthermore, an increasing number of risk genotypes of these two SNPs was associated with a higher risk of death in the MDACC, the NHS/HPFS, and their combined data sets (Ptrend<0.001, = 0.004 and <0.001, respectively). In the expression quantitative trait loci analysis, TKT rs9864057 G > A and DERA rs12297652 A > G were also significantly associated with higher mRNA expression levels in sun-exposed lower-leg skin (P = 0.043 and 0.006, respectively). Conclusions: These results suggest that these two potentially functional SNPs may be valuable prognostic biomarkers for CM survival, but larger studies are needed to validate these findings.Item Genetic variants of EML1 and HIST1H4E in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival(e-Century Publishing, 2021-06-15) He, Yuanmin; Liu, Hongliang; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Yang, Keming; Qureshi, Abrar A.; Han, Jiali; Wei, Qingyi; Epidemiology, School of Public HealthBoth in vivo and in vitro evidence has supported a key role of myeloid cells in immune suppression in melanoma and in promoting melanocytic metastases. Some single-nucleotide polymorphisms (SNPs) have been shown to predict cutaneous melanoma-specific survival (CMSS), but the association between genetic variation in myeloid cell-related genes and cutaneous melanoma (CM) patient survival remains unknown. Methods: we investigated associations between SNPs in myeloid cell-related pathway genes and CMSS in a discovery dataset of 850 CM patients and replicated the findings in another dataset of 409 CM patients. Results: we identified two SNPs (EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.56 (95% confidence interval =1.19-2.05, P=0.001) and 1.66 (1.22-2.26, P=0.001), respectively; so were their combined unfavorable alleles in a dose-response manner in both discovery and replication datasets (P trend<0.001 and 0.002, respectively). Additional functional analysis revealed that both EML1 rs10151787 G and HIST1H4E rs2069018 C alleles were associated with elevated mRNA expression levels in normal tissues. Conclusions: Our findings suggest that EML1 rs10151787 A>G and HIST1H4E rs2069018 T>C are independent prognostic biomarkers for CMSS.Item Genetic variants of SDCCAG8 and MAGI2 in mitosis‐related pathway genes are independent predictors of cutaneous melanoma‐specific survival(Wiley, 2021) He, Yuanmin; Liu, Hongliang; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Wei, Qingyi; Epidemiology, School of Public HealthMitosis 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 the mitotic rate as a category criterion of the tumor T-category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. As 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 = .001) and 1.45 (1.13-1.86, P = .003), respectively. Furthermore, their combined unfavorable alleles also predicted a poor survival in both discovery and validation datasets in a dose-response manner (Ptrend = .0006 and .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 Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival(MDPI, 2020-01-24) Zhou, Bingrong; Zhao, Yu Chen; Liu, Hongliang; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Li, Xin; Nan, Hongmei; Wei, Qingyi; Epidemiology, School of Public HealthBecause 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 Novel genetic variants of PIP5K1C and MVB12B of the endosome-related pathway predict cutaneous melanoma-specific survival(e-Century Publishing, 2020-10) Lu, Guiqing; Zhou, Bingrong; He, Yuanmin; Liu, Hongliang; Luo, Sheng; Amos, Christopher I.; Lee, Jeffrey E.; Yang, Keming; Qureshi, Abrar; Han, Jiali; Wei, Qingyi; Epidemiology, School of Public HealthEndosomes 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.