Browsing by Subject "pancreatic cancer susceptibility"

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    Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer.
    (Molecular carcinogenesis, 2020-05-05) Liu, Xiaowen; Qian, Danwen; Liu, Hongliang; Abbruzzese, James L; Luo, Sheng; Walsh, Kyle M; Wei, Qingyi
    Because the peroxisome proliferator-activated receptor (PPAR) signaling pathway is involved in development and progression of pancreatic cancer, we investigated associations between genetic variants of the PPAR pathway genes and pancreatic cancer risk by using three published genome-wide association study datasets including 8477 cases and 6946 controls of European ancestry. Expression quantitative trait loci (eQTL) analysis was also performed for correlations between genotypes of the identified genetic variants and messenger RNA (mRNA) expression levels of their genes by using available databases of the 1000 Genomes, TCGA, and GTEx projects. In the single-locus logistic regression analysis, we identified 1141 out of 17 532 significant single-nucleotide polymorphisms (SNPs) in 112 PPAR pathway genes. Further multivariate logistic regression analysis identified three independent, potentially functional loci (rs12947620 in MED1, rs11079651 in PRKCA, and rs34367566 in PRKCB) for pancreatic cancer risk (odds ratio [OR] = 1.11, 95% confidence interval [CI], [1.06-1.17], P = 5.46 × 10-5 ; OR = 1.10, 95% CI, [1.04-1.15], P = 1.99 × 10-4 ; and OR = 1.09, 95% CI, [1.04-1.14], P = 3.16 × 10-4 , respectively) among 65 SNPs that passed multiple comparison correction by false discovery rate (< 0.2). When risk genotypes of these three SNPs were combined, carriers with 2 to 3 unfavorable genotypes (NUGs) had a higher risk of pancreatic cancer than those with 0 to 1 NUGs. The eQTL analysis showed that rs34367566 A>AG was associated with decreased expression levels of PRKCB mRNA in 373 lymphoblastoid cell lines. Our findings indicate that genetic variants of the PPAR pathway genes, particularly MED1, PRKCA, and PRKCB, may contribute to susceptibility to pancreatic cancer.
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    Potential Functional Variants in SMC2 and TP53 in the AURORA Pathway Genes and Risk of Pancreatic Cancer.
    (Carcinogenesis, 2019-02-22) Feng, Yun; Liu, Hongliang; Duan, Bensong; Liu, Zhensheng; Abbruzzese, James; Walsh, Kyle M; Zhang, Xuefeng; Wei, Qingyi
    The AURORA pathway participates in mitosis and cell division, and alterations in mitosis and cell division can lead to carcinogenesis. Therefore, genetic variants in the AURORA pathway genes may be associated with susceptibility to pancreatic cancer. To test this hypothesis, we used three large, publically available pancreatic cancer genome-wide association studies (GWASs) datasets (PanScan I, II/III and PanC4) to assess the associations of 7,168 single nucleotide polymorphisms (SNPs) in a set of 62 genes of this pathway with pancreatic cancer risk (8,477 cases and 6,946 controls of European ancestry). We identify 15 significant pancreatic cancer risk-associated SNPs in three genes (SMC2, ARHGEF7 and TP53) after correction for multiple comparisons by a false discovery rate (FDR) < 0.20. Through further linkage disequilibrium analysis, SNP functional prediction and stepwise logistic regression analysis, we focused on three SNPs: rs3818626 in SMC2, rs79447092 in ARHGEF7 and rs9895829 in TP53. We found that these three SNPs were associated with pancreatic cancer risk [odds ratio (OR) = 1.12, 95% confidence interval (CI) = 1.07-1.17 and P = 2.20E-06 for the rs3818626 C allele; OR = 0.76, CI = 0.66-0.88 and P = 1.46E-04 for the rs79447092 A allele; and OR = 0.82, CI = 0.74-0.91 and P = 1.51E-04 for the rs9895829 G allele]. Their joint effect as the number of protective genotypes (NPGs) also showed a significant association with pancreatic cancer risk (trend test P ≤ 0.001). Finally, we performed an eQTL analysis and found that rs3818626 and rs9895829 were significantly associated with SMC2 and TP53 mRNA expression levels in 373 lymphoblastoid cell lines, respectively. In conclusion, these three representative SNPs may be potentially susceptibility loci for pancreatic cancer and warrant additional validation.