Browsing by Subject "Single-nucleotide polymorphism"

Now showing 1 - 6 of 6
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    Association study of genetic variation in DNA repair pathway genes and risk of basal cell carcinoma
    (Wiley, 2017-09-01) Lin, Yuan; Chahal, Harvind S.; Wu, Wenting; Cho, Hyunje G.; Ransohoff, Katherine J.; Song, Fengju; Tang, Jean Y.; Sarin, Kavita Y.; Han, Jiali; Epidemiology, School of Public Health
    DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets. After multiple testing corrections, we identified three SNPs (rs2805831 upstream of XPA: OR = 0.93, P = 1.35 × 10-6 ; rs659857 in exon of MUS81: OR = 1.06, P = 3.09 × 10-6 and rs57343616 in 3' UTR of NABP2: OR = 1.11, P = 6.47 × 10-6 ) as significantly associated with BCC risk in meta-analysis, and all of them were nominally significant in both data sets. Furthermore, rs659857 [T] was significantly associated with decreased expression of MUS81 mRNA in the expression quantitative trait locus (eQTL) analysis. Our findings suggest that the inherited common variation in three DNA repair genes-XPA, MUS81 and NABP2-may be involved in the development of BCC. To our knowledge, our study is the first report thoroughly examining the effects of SNPs across DNA repair pathway genes on BCC risk based on a genome-wide association meta-analysis.
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    Genetic variants in the folate metabolic pathway genes predict melanoma-specific survival
    (Oxford University Press, 2020-10) Dai, W.; Liu, H.; Liu, Y.; Xu, X.; Qian, D.; Luo, S.; Cho, E.; Zhu, D.; Amos, C.I.; Fang, S.; Lee, J.E.; Li, X.; Nan, H.; Li, C.; Wei, Q.; Epidemiology, School of Public Health
    Background: 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 (GWASs) 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. Objectives: To examine associations between SNPs in folate metabolic pathway genes and CMSS. Methods: We comprehensively evaluated 2645 (422 genotyped and 2223 imputed) common SNPs in folate metabolic pathway genes from a published GWAS of 858 patients from The University of Texas MD 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 (11·7%) 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 the biological 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. Conclusions: 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. What is already known about this topic? Existing data show that survival rates vary among patients with melanoma with similar clinical characteristics; therefore, it is necessary to identify additional complementary biomarkers for melanoma-specific prognosis. A hypothesis-driven approach, by pooling the effects of single-nucleotide polymorphisms (SNPs) in a specific biological pathway as genetic risk scores, may provide a prognostic utility, and genetic variants of genes in folate metabolism have been reported to be associated with cancer risk. What does this study add? Two genetic variants in the folate metabolic pathway genes, MTHFD1 rs1950902 and ALPL rs10917006, are significantly associated with cutaneous melanoma-specific survival (CMSS). What is the translational message? The identification of genetic variants will make a risk-prediction model possible for CMSS. The SNPs in the folate metabolic pathway genes, once validated in larger studies, may be useful in the personalized management and treatment of patients with cutaneous melanoma.
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    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 Health
    Background: 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.
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    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 Health
    Both 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.
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    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, Richard M. Fairbanks School of Public Health
    Mitosis 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.
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    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 Health
    Because 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.