Browsing by Author "Lin, Lijuan"

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    APOB Genotypes and CDH13 Haplotypes in the Cholesterol-Related Pathway Genes Predict 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, 2020-04) Deng, Wei; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey; Glass, Carolyn; Su, Li; Lin, Lijuan; Christiani, David C; Wei, Qingyi
    BACKGROUND:Several oncogenic signals are involved in the synthesis, metabolism, transportation, and modulation of cholesterol. However, the roles of genetic variants of the cholesterol pathway genes in cancer survival remain unclear. METHODS:We investigated associations between 26,781 common SNPs in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping data from two published genome-wide association studies. We used multivariate Cox proportional hazards regression and expression quantitative trait loci analyses to identify survival-associated SNPs and their correlations with the corresponding mRNA expression, respectively. We also used the Kaplan-Meier survival analysis and bioinformatics functional prediction to further evaluate the identified independent SNPs. RESULTS:We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C, and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets. When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with worse survival (P trend < 0.0001). In addition, both APOB rs1801701T
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    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, Qingyi
    Accumulating 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.
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    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, Qingyi
    Although 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.
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    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, Qingyi
    The 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.