Key Laboratory of Fertility Preservation and Maintenance, School of Basic Medicine and the General Hospital, Ningxia Medical University, Yinchuan, China.
Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham.
Cancer Sci. 2019 Jun;110(6):2022-2032. doi: 10.1111/cas.14017. Epub 2019 May 6.
Pancreatic cancer (PanC) is one of the most lethal solid malignancies, and metastatic PanC is often present at the time of diagnosis. Although several high- and low-penetrance genes have been implicated in PanC, their roles in carcinogenesis remain only partially elucidated. Because the nuclear factor erythroid2-related factor2 (NRF2) signaling pathway is involved in human cancers, we hypothesize that genetic variants in NRF2 pathway genes are associated with PanC risk. To test this hypothesis, we assessed associations between 31 583 common single nucleotide polymorphisms (SNP) in 164 NRF2-related genes and PanC risk using three published genome-wide association study (GWAS) datasets, which included 8474 cases and 6944 controls of European descent. We also carried out expression quantitative trait loci (eQTL) analysis to assess the genotype-phenotype correlation of the identified significant SNP using publicly available data in the 1000 Genomes Project. We found that three novel SNP (ie, rs3124761, rs17458086 and rs1630747) were significantly associated with PanC risk (P = 5.17 × 10 , 5.61 × 10 and 5.52 × 10 , respectively). Combined analysis using the number of unfavorable genotypes (NUG) of these three SNP suggested that carriers of two to three NUG had an increased risk of PanC (P < 0.0001), compared with those carrying zero to one NUG. Furthermore, eQTL analysis showed that both rs3124761 T and rs17458086 C alleles were associated with increased mRNA expression levels of SLC2A6 and SLC2A13, respectively (P < 0.05). In conclusion, genetic variants in NRF2 pathway genes could play a role in susceptibility to PanC, and further functional exploration of the underlying molecular mechanisms is warranted.
胰腺癌（PanC）是最致命的实体恶性肿瘤之一，转移性 PanC 通常在诊断时就已存在。尽管已经有几个高和低外显率的基因被牵连到 PanC 中，但它们在致癌作用中的作用仍部分阐明。由于核因子红细胞 2 相关因子 2（NRF2）信号通路参与人类癌症，我们假设 NRF2 通路基因中的遗传变异与 PanC 风险相关。为了验证这一假设，我们使用三个已发表的全基因组关联研究（GWAS）数据集评估了 164 个 NRF2 相关基因中的 31583 个常见单核苷酸多态性（SNP）与 PanC 风险之间的关联，这些数据集包括 8474 例欧洲裔病例和 6944 例对照。我们还进行了表达数量性状基因座（eQTL）分析，使用 1000 基因组计划中公开的数据评估了鉴定出的显著 SNP 的基因型-表型相关性。我们发现三个新的 SNP（即 rs3124761、rs17458086 和 rs1630747）与 PanC 风险显著相关（P=5.17×10-8、5.61×10-8 和 5.52×10-8）。使用这三个 SNP 的不利基因型（NUG）数量进行联合分析表明，与携带零至一个 NUG 的个体相比，携带两个至三个 NUG 的个体 PanC 风险增加（P<0.0001）。此外，eQTL 分析显示，rs3124761 的 T 等位基因和 rs17458086 的 C 等位基因分别与 SLC2A6 和 SLC2A13 的 mRNA 表达水平增加相关（P<0.05）。总之，NRF2 通路基因中的遗传变异可能在 PanC 的易感性中起作用，需要进一步探索潜在的分子机制的功能。
