外周血白细胞SLC45A4和AHSP基因甲基化与乳腺癌关系的病例对照研究

Methylation of SLC45A4 and AHSP gene in peripheral blood leukocytes and the risks of breast cancer:a case⁃control study

目的探究外周血白细胞溶质载体家族45成员4(solute carrier family 45 member 4,SLC45A4)和α血红蛋白稳定蛋白(αhemoglobin stabilizing protein,AHSP)基因甲基化与乳腺癌发病的关系。方法通过差异甲基化分析等方法在GSE51032、GSE104942和GSE89093数据集中筛选与乳腺癌发病潜在相关的基因。采用病例对照研究,纳入545例乳腺癌患者和524例非乳腺癌对照作为研究对象。使用MethylTarget靶向测序检测目标基因甲基化并分析其与乳腺癌的关系。结果本研究共筛选出4个基因,控制混杂因素后,SLC45A4和AHSP高甲基化与乳腺癌关系的ORadj分别为0.218(95%CI:0.158~0.299)和0.535(95%CI:0.384~0.741)。在不同亚组中SLC45A4高甲基化与乳腺癌的关联仍有统计学意义,ORadj最高为0.427(95%CI:0.270~0.679),最低为0.153(95%CI:0.085~0.274),而AHSP高甲基化仅在管腔A型(Luminal A)、管腔B型(Luminal B)、雌激素受体阳性(estrogen receptor+,ER+)和≤60岁年龄组中与乳腺癌的关联有统计学意义。异质核糖核酸蛋白C(heterogeneous nuclear ribonucleoproteins C,HNRNPC)甲基化与乳腺癌的关系与公共数据结果相反,ORadj为0.747(95%CI:0.569~0.980),锌指蛋白425(zinc finger protein 425,ZNF425)甲基化与乳腺癌的关联无统计学意义(P=0.158)。结论外周血白细胞SLC45A4和AHSP基因高甲基化可能是乳腺癌发病的保护因素。

Objective To investigate the relationship between peripheral blood leukocyte solute carrier family 45 member 4(SLC45A4)and alpha hemoglobin stabilizing protein(AHSP)gene methylation and the risk of breast cancer.Methods Datasets GSE51032,GSE104942 and GSE89093 were used to identify genes that potentially associated with the risk of breast cancer through differential methylation analysis and other methods.A case⁃control study with 545 breast cancer patients and 524 cancer⁃free controls was carried out to validate the correlation between the methylation levels of the screened genes and breast cancer susceptibility.Results In this study,four genes were selected.After controlling for potential confounding factors,hypermethylation of SLC45A4 and AHSP was associated with lower breast cancer risk(ORadj=0.218,95%CI:0.158-0.299;ORadj=0.535,95%CI:0.384-0.741,respectively).The association of SLC45A4 hypermethylation with breast cancer remained statistically significant in different subgroups.The maximum value of ORadj was 0.427(95%CI:0.270-0.679)and the minimum value was 0.153(95%CI:0.085-0.274).However,the association of AHSP hypermethylation with breast cancer risk was statistically significant only in Luminal A,Luminal B subtypes,estrogen receptor+(ER+),and≤60 age group.The association of heterogeneous nuclear ribonucleoproteins C(HNRNPC)methylation with the risk of breast cancer in our case⁃control study was inconsistent to the results of public datasets(ORadj=0.747,95%CI:0.569-0.980).There was no statistically significant association between zinc finger protein 425(ZNF425)methylation and breast cancer risk(P=0.158).Conclusions Hypermethylation of SLC45A4 and AHSP in peripheral blood leukocytes may serve as protective factors for breast cancer.