Browsing by Subject "genetic susceptibility"

Now showing 1 - 3 of 3

Open Access
A pleiotropic ATM variant (rs1800057 C>G) is associated with risk of multiple cancers.
(Carcinogenesis, 2021-10-13) Qian, Danwen; Liu, Hongliang; Zhao, Lingling; Luo, Sheng; Walsh, Kyle M; Huang, Jiaoti; Li, Chuan-Yuan; Wei, Qingyi
ATM (ataxia-telangiectasia mutated) is an important cell-cycle checkpoint kinase required for cellular response to DNA damage. Activated by DNA double strand breaks, ATM regulates the activities of many downstream proteins involved in various carcinogenic events. Therefore, ATM or its genetic variants may have a pleiotropic effect in cancer development. We conducted a pleiotropic analysis to evaluate associations between genetic variants of ATM and risk of multiple cancers. With genotyping data extracted from previously published genome-wide association studies of various cancers, we performed multivariate logistic regression analysis, followed by a meta-analysis for each cancer site, to identify cancer risk-associated single-nucleotide polymorphisms (SNPs). In the ASSET two-sided analysis, we found that two ATM SNPs were significantly associated with risk of multiple cancers. One tagging SNP (rs1800057 C>G) was associated with risk of multiple cancers (two-sided P=5.27×10 -7). Because ATM rs1800057 is a missense variant, we also explored the intermediate phenotypes through which this variant may confer risk of multiple cancers and identified a possible immune-mediated effect of this variant. Our findings indicate that genetic variants of ATM may have a pleiotropic effect on cancer risk and thus provide an important insight into common mechanisms of carcinogenesis.
Open Access
Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.
(Molecular carcinogenesis, 2019-11-12) Tang, Dongfang; Zhao, Yu Chen; Qian, Danwen; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Glass, Carolyn; Gao, Wen; Wei, Qingyi
The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.
Open Access
Potentially functional genetic variants in PLIN2, SULT2A1 and UGT1A9 genes of the ketone pathway and survival of nonsmall cell lung cancer.
(International journal of cancer, 2020-02-18) Tang, Dongfang; Zhao, Yu C; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey M; Glass, Carolyn; Su, Li; Shen, Sipeng; Christiani, David C; Gao, Wen; Wei, Qingyi
The ketone metabolism pathway is a principle procedure in physiological homeostasis and induces cancer cells to switch between glycolysis and oxidative phosphorylation for energy production. We conducted a two-phase analysis for associations between genetic variants in the ketone metabolism pathway genes and survival of nonsmall cell lung cancer (NSCLC) by analyzing genotyping data from two published genome-wide association studies (GWASs). In the discovery, we used a genotyping dataset from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial in the multivariable Cox proportional hazards regression analysis. We used Bayesian false discovery probability (≤0.80) for multiple testing correction to evaluate associations between 25,819 (2,176 genotyped and 23,643 imputed) single-nucleotide polymorphisms (SNPs) in 162 genes and survival of 1,185 NSCLC patients. Subsequently, we validated the identified significant SNPs with an additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility GWAS study. Finally, we found that three independent and potentially functional SNPs in three different genes (i.e., PLIN2 rs7867814 G>A, SULT2A1 rs2547235 C>T and UGT1A9 rs2011404 C>T) were independently associated with risk of death from NSCLC, with a combined hazards ratio of 1.22 [95% confidence interval = 1.09-1.36 and p = 0.0003], 0.82 (0.74-0.91 and p = 0.0002) and 1.21 (1.10-1.33 and p = 0.0001), respectively. Additional expression quantitative trait loci analysis found that the survival-associated PLIN2 rs7867814 GA + AA genotypes, but not the genotypes of other two SNPs, were significantly associated with increased mRNA expression levels (p = 0.005). These results indicated that PLIN2 variants may be potential predictors of NSCLC survival through regulating the PLIN2 expression.