子宫内膜癌同源重组修复缺陷相关基因表达及与临床病理特征、免疫浸润的关系

Expression of genes associated with homologous recombinant repair defects in endometrial cancer and its relationship with clinicopathologic features and immune infiltration

目的探究子宫内膜癌患者同源重组修复(HRR)缺陷相关基因表达及其与临床病理特征、免疫浸润的关系。方法回顾性选取2018年6月至2020年6月在山东第一医科大学附属人民医院进行手术治疗的子宫内膜癌患者53例(子宫内膜癌)为研究对象,另选取健康体检女性50例为健康对照组,收集53例子宫内膜癌患者临床病理特征,实时荧光定量-聚合酶链反应(RT-PCR)法检测研究对象外周血人乳腺癌易感基因1(BRCA1)、肿瘤抑制基因-第10染色体同源丢失性磷酸酶-张力蛋白基因(PTEN)信使RNA(mRNA)表达水平,采用流式细胞仪检测外周血单核细胞中CD_(4)^(+)T细胞各亚群比例;Pearson分析外周血BRCA1、PTEN mRNA表达与CD_(4)^(+)T细胞各亚群的相关性;COX风险回归模型分析子宫内膜癌预后影响因素。结果子宫内膜癌组患者外周血BRCA1、PTEN mRNA表达水平均高于健康对照组(2.87±0.65比1.02±0.13、3.25±0.74比1.01±0.20),差异有统计学意义(P<0.01)。子宫内膜癌组患者外周血辅助性T细胞2(Th2)、辅助性T细胞17(Th17)、调节性T细胞(Treg)、辅助性T细胞22(Th22)比例明显高于健康对照组[(10.72±1.33)%比(5.43±0.80)%、(9.78±0.80)%比(3.31±0.62)%、(10.81±1.29)%比(5.74±0.69)%、(6.09±0.70)%比(3.09±0.73)%],辅助性T细胞1(Th1)比例明显低于健康对照组[(5.54±0.90)%比(13.07±2.55)%],差异有统计学意义(P<0.01)。肌层浸润深度≥1/2、组织学分级G_(2)-G_(3)、有淋巴结转移、国际妇产科学联合会(FIGO)分期Ⅲ~Ⅳ期的患者外周血BRCA1、PTEN mRNA表达水平明显高于肌层浸润深度<1/2、组织学分级G 1、无淋巴结转移、FIGO分期Ⅰ~Ⅱ期的患者,差异有统计学意义(P<0.01或<0.05)。外周血BRCA1、PTEN mRNA分别与Th2、Th17、Treg、Th22比例呈明显正相关(P<0.01),与Th1比例呈负相关(P<0.01)。COX风险回归分析结果显示,组织学分级、FIGO分期、肌层浸润深度、有淋巴结转移外周血BRCA1 mRNA表达、外周血PTEN mRNA表达均为子宫内膜癌预后独立影响因素(P<0.01或<0.05)。结论HRR缺陷相关基因BRCA1、PTEN mRNA在子宫内膜癌患者中呈现高水平,且与肌层浸润深度、组织学分级、有淋巴结转移、FIGO分期密切相关,并可通过影响子宫内膜癌患者的免疫微环境,进而影响疾病进展和预后。

ObjectiveTo explore the expression of homologous recombination repair(HRR)deficiency related genes in endometrial cancer and their relationship with clinical pathological features and immune infiltration.MethodsA total of 53 patients with endometrial cancer(endometrial cancer group)who underwent surgical treatment at the Affiliated People′s Hospital of Shandong First Medical University from June 2018 to June 2020 were selected as the study subjects.Clinical data of the patients were retrospectively analyzed,and 50 healthy women who underwent physical examinations were selected as the control group.Clinical and pathological characteristics of 53 patients with endometrial cancer were collected,and real-time fluorescence quantitative polymerase chain reaction(RT-PCR)was performed Methods The mRNA expressions of human breast cancer susceptibility gene 1(BRCA1),tumor suppressor gene homologous loss phosphatase tensin gene(PTEN)on chromosome 10 in the peripheral blood of the subjects were detected,and the proportions of CD_(4)^(+)T cell subsets in peripheral blood monocytes were detected by flow cytometry;Pearson analysis of the correlation between peripheral blood BRCA1,PTEN mRNA expression and various subsets of CD_(4)^(+)T cell;Analysis of prognostic factors for endometrial cancer using COX risk regression model.ResultsThe peripheral blood BRCA1 and PTEN mRNA expression levels in patients with endometrial cancer were higher than those in the healthy control group:2.87±0.65 vs.1.02±0.13,3.25±0.74 vs.1.01±0.20,and the differences were statistically significant(P<0.01).The proportion of peripheral blood helper T cell-2(Th2),helper T cell-17(Th17),regulatory T cell(Treg)and helper T cell-22(Th22)in patients with endometrial cancer was significantly higher than that in the healthy control group:(10.72±1.33)%vs.(5.43±0.80)%,(9.78±0.80)%vs.(3.31±0.62)%,(10.81±1.29)%vs.(5.74±0.69)%,(6.09±0.70)%vs.(3.09±0.73)%,and the proportion of helper T cell-1(Th1)was significantly lower than that in the healthy control group:(5.54±0.90)%vs.(13.07±2.55)%,the difference was statistically significant(P<0.01).The peripheral blood BRCA1 and PTEN mRNA expression levels were significantly higher in patients with muscle infiltration depth≥1/2,histological grade G_(2) to G_(3),lymph node metastasis,and International Federation of Obstetrics and Gynecology(FIGO)stageⅢtoⅣthan in patients with muscle infiltration depth<1/2,histological grade G_(1),no lymph node metastasis,and FIGO stageⅠtoⅡ,with statistical significance(P<0.01 or<0.05).Peripheral blood BRCA1 and PTEN mRNA were significantly positively correlated with Th2,Th17,Treg and Th22 ratios(P<0.01),and negatively correlated with Th1 ratios(P<0.01).COX risk regression analysis showed that histological grading,FIGO staging,depth of muscle infiltration,peripheral blood BRCA1 and PTEN mRNA expression with lymph node metastasis were all independent prognostic factors for endometrial cancer(P<0.01 or<0.05).ConclusionsHRR deficiency related genes BRCA1 and PTEN mRNA exhibit high levels in patients with endometrial cancer,and are closely related to muscle infiltration depth,histological grading,lymph node metastasis,and FIGO staging.They can also affect the immune microenvironment of endometrial cancer patients,thereby affecting disease progression and prognosis.