Browsing by Author "Ge, Jie"
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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 TKT and DERA in the nicotinamide adenine dinucleotide phosphate pathway predict melanoma survival.(European journal of cancer (Oxford, England : 1990), 2020-07-09) 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, QingyiBACKGROUND: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 Open Access Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.(International journal of cancer, 2019-09) Ge, Jie; Liu, Hongliang; Qian, Danwen; Wang, Xiaomeng; Moorman, Patricia G; Luo, Sheng; Hwang, Shelley; Wei, QingyiA recent hypothesis-free pathway-level analysis of genome-wide association study (GWAS) datasets suggested that the overall genetic variation measured by single nucleotide polymorphisms (SNPs) in the nucleotide excision repair (NER) pathway genes was associated with breast cancer (BC) risk, but no detailed SNP information was provided. To substantiate this finding, we performed a larger meta-analysis of 14 previously published GWAS datasets in the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) study with 53,107 subjects of European descent. Using a hypothesis-driven approach, we selected 138 candidate genes from the NER pathway using the "Molecular Signatures Database (MsigDB)" and "PathCards". All SNPs were imputed using IMPUTE2 with the 1000 Genomes Project Phase 3. Logistic regression was used to estimate BC risk, and pooled ORs for each SNP were obtained from the meta-analysis using the false discovery rate for multiple test correction. RegulomeDB, HaploReg, SNPinfo and expression quantitative trait loci (eQTL) analysis were used to assess the SNP functionality. We identified four independent SNPs associated with BC risk, BIVM-ERCC5 rs1323697_C (OR = 1.06, 95% CI = 1.03-1.10), GTF2H4 rs1264308_T (OR = 0.93, 95% CI = 0.89-0.97), COPS2 rs141308737_C deletion (OR = 1.06, 95% CI = 1.03-1.09) and ELL rs1469412_C (OR = 0.93, 95% CI = 0.90-0.96). Their combined genetic score was also associated with BC risk (OR = 1.12, 95% CI = 1.08-1.16, ptrend < 0.0001). The eQTL analysis revealed that BIVM-ERCC5 rs1323697 C and ELL rs1469412 C alleles were correlated with increased mRNA expression levels of their genes in 373 lymphoblastoid cell lines (p = 0.022 and 2.67 × 10-22 , respectively). These SNPs might have roles in the BC etiology, likely through modulating their corresponding gene 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.