转化生长因子β1基因多态性与左乳腺癌术后放疗发生心脏毒性有关

郑国红.转化生长因子β1基因多态性与左乳腺癌术后放疗发生心脏毒性有关[J].内科急危重症杂志,2023,29(4):310-315

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DOI：10.11768/nkjwzzzz20230412

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基金项目:河北省卫生健康委科研基金项目（No：20190169）

作者	单位	E-mail
郑国红	河北省唐山市人民医院	wangxiaohongrenmin@163.com

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中文摘要:

摘要目的：探讨转化生长因子（TGF）-β1基因的2个位点rs12985162（G＞A）和rs10417924（T＞C）多态性及表达水平与左乳腺癌术后放疗发生心脏毒性的相关性。方法：纳入接受保乳术或改良根治术后放疗的104例女性左乳腺癌患者和100例右乳腺癌患者为研究对象，应用全自动化学发光免疫分析仪检测患者血清心肌肌钙蛋白I（cTnI）和N末端 B 型利钠肽前体（NT- proBNP）水平，采用毛细管电泳和片段分析技术对TGF-β基因的2个单核苷酸多态性位点rs12985162、rs10417924进行基因分型。采用实时荧光定量聚合酶链式反应（RT-PCR）测定TGF-β基因mRNA相对表达量。对所有患者定期随访，记录心脏毒性事件发生情况，截止至放疗结束后6个月。结果：左乳腺癌患者的心脏毒性发生比例显著高于右乳腺癌患者（36.5% vs 9.0%，χ2=21.804，P＜0.001）。发生心脏毒性的左乳腺癌患者在临床分期和术后行放疗构成比方面与心脏无毒性患者比较，差异有统计学意义（P均＜0.05）。左乳腺癌患者心脏毒性组和无毒性组的TGF-β的rs12985162位点GG、GA、AA基因型分布有显著差异（χ2=7.527，P=0.023）。采用Logistic回归校正临床分期和术后是否行化疗后发现，AA或GA基因型左乳腺癌患者发生心脏毒性的风险显著高于GG基因型（P＜0.05）。对于rs10417924位点，左乳腺癌患者心脏毒性组和无毒性组的TT、TC、CC基因型分布有显著差异（χ2=6.324，P=0.042）。Logistic回归结果显示，CC或TC基因型左乳腺癌患者发生心脏毒性的风险显著高于TT基因型（P＜0.05）。rs12985162和rs10417924位点的等位基因在左乳腺癌患者心脏毒性组和无毒性组中的分布有显著性差异（P均＜0.05）。左乳腺癌患者心脏毒性组的TGF-β1基因mRNA相对表达量显著高于无毒性组 [（3.44±0.38) vs (1.83±0.15)，t=8.643，P＜0.001]。左乳腺癌患者心脏毒性患者中rs12985162位点AA+GA基因型患者的TGF-β1mRNA相对表达量显著高于GG基因型（t=4.124，P＜0.001）。rs10417924位点CC+TC基因型与TT型比较， TGF-β1基因mRNA相对表达量差异无统计学意义（t=1.864，P=0.284）。结论：TGF-β1基因多态性与左乳腺癌术后放疗发生心脏毒性有关。

英文摘要:

Abstract Objective: To investigate the correlation between the polymorphism and expression levels of rs12985162 (C> T) and RS10417924 (C> T) of the transforming growth factor-β1 (TGF-β1) gene and cardiotoxicity after radiotherapy for left breast cancer. Methods: A total of 104 female left breast cancer patients and 100 right breast cancer patients who received modified radical postoperative radiotherapy were included as the research objects. The serum levels of cardiac troponin I (cTnI) and N-terminal B-type natriuretic peptide precursor (NT-probNP) were detected by automatic chemiluminescence immunoanalyzer. Two SNPs (rs12985162 and RS10417924) of TGF-β gene were genotyped by capillary electrophoresis and fragment analysis. The mRNA relative expression level of TGF-β gene was detected by quantitative real-time fluorescence quantitative polymerase chain reaction. All patients were followed up regularly from the beginning of radiotherapy to 6 months after radiotherapy. Quring the follow-up period, echocardiography was used to measure the left ventricular short axis shortening rate (LVEF). Results: A total of 38 (36.5%) patients with left breast cancer developed cardiotoxicity. Of the 100 patients with right breast cancer, 9 (9.0%) developed cardiotoxicity. The incidence of cardiotoxicity in left breast cancer patients was significantly higher than that in right breast cancer patients, and the difference was statistically significant (χ2=21.804, P< 0.001). There were significant differences in clinical stage and postoperative radiotherapy between left breast cancer patients with and without cardiotoxicity (P< 0.05). For rs12985162, there were significant differences in the distribution of GG, GA and AA genotypes between the cardiotoxic group and the non-toxic group (χ2=7.527, P= 0.023). The results of Logistic regression correction for clinical staging and postoperative chemotherapy showed that compared with GG genotype, GA genotype in left breast cancer patients had a significantly increased risk of cardiac toxicity (P< 0.05), and AA or GA genotype in left breast cancer patients had a significantly higher risk of cardiac toxicity than GG genotype (P< 0.05). For rs10417924 site, TT, TC and CC genotype distribution of left breast cancer patients was significantly different between the cardiotoxic group and the non-toxic group (χ2=6.324, P=0.042). Logistic regression showed that CC or TC carriers in left breast cancer patients had a significantly higher risk of cardiotoxicity than TT carriers (P<0.05). The alleles of rs12985162 and rs10417924 were significantly different in the left breast cancer patients between the cardiotoxicity group and the non-toxic group (all P< 0.05). The mRNA relative expression level of TGF-β1 gene in the cardiotoxicity group in the left breast cancer patients was 3.44±0.38, which was significantly higher than that in the non-toxic group (1.83±0.15) (P= 8.643, P< 0.001). The mRNA relative expression level of TGF-β1 gene in rs12985162 AA+GA genotype carriers was significantly higher than that in GG genotype carriers in left breast cancer patients with cardiotoxicity (t=4.124, P< 0.001). There was no significant difference in TGF-β1 mRNA relative expression level in left breast cancer patients at rs10417924 site between CC+TC genotype group and TT genotype group (t=1.864, P=0.284). Conclusion: TGF-β1 gene polymorphism is associated with cardiotoxicity of postoperative radiotherapy for left breast cancer.