Browsing by Subject "single-nucleotide polymorphism"

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    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 Health
    A 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.
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    Genetic variants in the integrin signaling pathway genes predict cutaneous melanoma survival
    (Wiley, 2017-03-15) Li, Hongyu; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Xu, Yinghui; Wu, Wenting; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Han, Jiali; Wei, Qingyi; Epidemiology, School of Public Health
    To identify genetic variants involved in prognosis of cutaneous melanoma (CM), we investigated associations of single nucleotide polymorphisms (SNPs) of genes in the integrin signaling pathway with CM survival by re-analyzing a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center (MDACC), and then validated significant SNPs in another GWAS from Harvard University. In the MDACC study, 1,148 SNPs were significantly associated with CM-specific survival (CMSS) (P ≤ 0.050 and false-positive report probability ≤ 0.20), and nine SNPs were validated in the Harvard study (P ≤ 0.050). Among these, three independent SNPs (i.e., DOCK1 rs11018104 T>A, rs35748949 C>T and PAK2 rs1718404 C>T) showed a predictive role in CMSS, with an effect-allele attributed adjusted hazards ratio [adjHR of 1.50 (95% confidence interval (CI) = 1.18-1.90, P = 7.46E-04), 1.53 (1.18-1.97, 1.18E-03) and 0.58 (0.45-0.76, 5.60E-05), respectively]. Haplotype analysis revealed that a haplotype carrying two risk alleles A-T in DOCK1 was associated with the poorest survival in both MDACC (adjHR=1.73, 95% CI = 1.19-2.50, P = 0.004) and Harvard (adjHR = 1.95, 95% CI=1.14-3.33, P = 0.010) studies. In addition, patients with an increasing number of unfavorable genotypes (NUGs) for these three SNPs had a poorer survival. Incorporating NUGs with clinical variables showed a significantly improved ability to classify CMSS (AUC increased from 86.8% to 88.6%, P = 0.031). Genetic variants in the integrin signaling pathway may independently or jointly modulate the survival of CM patients. Further large, prospective studies are needed to validate these findings.
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    Genetic variants in the metzincin metallopeptidase family genes predict melanoma survival
    (Wiley, 2017) Xu, Yinghui; Wang, Yanru; Liu, Hongliang; Shi, Qiong; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Hyslop, Terry; Li, Xin; Han, Jiali; Wei, Qingyi; Department of Epidemiology, School of Public Health
    Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.
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    Genetic Variants in WNT2B and BTRC Predict Melanoma Survival
    (Elsevier, 2017) Shu, Qiong; Liu, Hongliang; Han, Peng; Li, Chunying; Wang, Yanru; Wu, Wenting; Zhu, Dakai; Amos, Christopher I.; Fang, Shenying; Lee, Jeffrey E.; Han, Jiali; Wei, Qingyi; Department of Epidemiology, Richard M. Fairbanks School of Public Health
    Cutaneous melanoma (CM) is the most lethal skin cancer. The Wnt pathway has an impact on development, invasion and metastasis of CM, thus likely affecting CM prognosis. Using data from a published genome-wide association study (GWAS) from The University of Texas M.D. Anderson Cancer Center, we assessed the associations of 19,830 common single-nucleotide polymorphisms (SNPs) in 151 Wnt pathway autosomal genes with CM-specific survival (CMSS) and then validated significant SNPs in another GWAS from Harvard University. In the single-locus analysis, 1,855 SNPs were significantly associated with CMSS at P < 0.05, of which 547 SNPs were still considered noteworthy after the correction by the false positive report probability. In the replication, two SNPs remained significantly associated with CMSS after multiple comparison correction. By performing functional prediction and stepwise selection, we identified two independent SNPs (i.e., WNT2B rs1175649 G>T and BTRC rs61873997 G>A) that showed a predictive role in CMSS, with an effect-allele-attributed hazards ratio [adjHR of 1.99 (95% confidence interval (CI) = 1.41-2.81, P = 8.10E-05) and 0.61 (0.46-0.80, 3.12E-04), respectively]. Collectively, these variants in the Wnt pathway genes may be biomarkers for outcomes of CM patients, if validated by larger studies.
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    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 Health
    Endosomes 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.