Genetic Variant of PP2A Subunit Gene Confers an Increased Risk of Primary Liver Cancer in Chinese.
Genetic Variant of PP2A Subunit Gene Confers an Increased Risk of Primary Liver Cancer in Chinese.
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DOI：
10.2147/pgpm.s335555
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发表时间：
2021
影响因子：
1.9
通讯作者：
Nong Q
中科院分区：
文献类型：
--
作者：
Wang Y;Huang Q;Huang X;Zhao H;Guan B;Ban K;Zhu X;Ma Z;Tang Y;Su Z;Nong Q
蛋白磷酸酶 2A（PP2A，一种丝氨酸/苏氨酸磷酸酶）在许多类型的癌症中经常失活，包括原发性肝癌 (PLC)。据报道，PP2A 亚基的遗传变异与多种癌症的风险相关，但在 PLC 中很少见。本研究旨在评估中国人 PP2A 亚基基因的功能多态性与 PLC 风险之间的关联。在中国南方广西省总共 541 名 PLC 患者和 547 名对照者的病例对照研究中，我们对 6 个假定的功能多态性进行了基因分型（rs10421191G>A、rs11453459del>insG、rs1560092T>G、rs7840855C>T、rs1255722G>A 和使用基质辅助激光解吸/电离飞行时间 (MALDI-TOF) 质谱平台分析三个 PP2A 亚基基因（PPP2R1A、PPP2R2A 和 PPP2R5E）的 rs10151527A>C）。与 del/del 基因型相比，PPP2R1A 的 rs11453459insG 变异基因型 (ins/ins+del/ins) 被发现与 PLC 风险增加显着相关（调整后 OR = 1.290，95% CI = 1.009–1.650），并且插入 G 等位基因的数量以剂量依赖性方式起作用（Ptrend = 0.007）。分层分析显示，rs11453459insG 变异基因型的影响在饮用池塘沟渠水的亚组中（调整后 OR = 3.051，95% CI = 1.264–7.364）比从不喝水的亚组更明显（P = 0.041）。 rs11453459 del/ins基因型携带者肝癌组织中PPP2R1A mRNA表达水平显着低于del/del基因型携带者(P=0.021)。此外，我们使用池塘沟渠水中存在的致癌物质微囊藻毒素-LR处理人外周血单核细胞，发现rs11453459insG变异基因型携带者的细胞比del/del基因型携带者的细胞诱导更多的DNA氧化损伤（P < 0.001）。这些发现表明，PPP2R1A rs11453459del>insG 多态性与 PLC 风险增加相关，特别是对于有饮用池塘沟渠水史的人。这种插入/缺失多态性可能是中文 PLC 的易感生物标志物。
Protein phosphatase 2A (PP2A, a serine/threonine phosphatase) is frequently inactivated in many types of cancer, including primary liver cancer (PLC). Genetic variations in PP2A subunits have been reported to be associated with the risk of many types of cancer but rarely in PLC. This study aims to assess the association between functional polymorphisms of PP2A subunit genes and the risk of PLC in Chinese. In a case-control study with a total of 541 PLC patients and 547 controls in Guangxi province of Southern China, we genotyped six putatively functional polymorphisms (rs10421191G>A, rs11453459del>insG, rs1560092T>G, rs7840855C>T, rs1255722G>A and rs10151527A>C) of three PP2A subunit genes (PPP2R1A, PPP2R2A and PPP2R5E) using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform. The rs11453459insG variant genotypes (ins/ins+del/ins) of PPP2R1A were found to be significantly associated with an increased risk of PLC compared with the del/del genotype (adjusted OR = 1.290, 95% CI = 1.009–1.650), and the number of insert G allele worked in a dose-dependent manner (Ptrend= 0.007). The stratified analysis showed that the effects of rs11453459insG variant genotypes were more evident in the subgroup who drink pond-ditch water (adjusted OR = 3.051, 95% CI = 1.264–7.364) than those never drink (P = 0.041). The carriers of rs11453459 del/ins genotype had a significantly lower level of PPP2R1A mRNA expression in liver cancer tissues than those of the del/del genotype (P = 0.021). Furthermore, we used microcystin-LR, a carcinogen presents in the pond-ditch water, to treat human peripheral blood mononuclear cells and found that the cells from carriers of rs11453459insG variant genotypes induced more DNA oxidative damages than those from the del/del genotype carriers (P < 0.001). These findings suggest that the PPP2R1A rs11453459del>insG polymorphism is associated with an increased risk of PLC, especially for persons with a history of drinking pond-ditch water. This insertion/deletion polymorphism may be a susceptible biomarker for PLC in Chinese.