This study included 1453 patients with newly diagnosed breast cancer from the multicentric prospective Sweden Cancerome Analysis Network - Breast study. Total serum selenium, selenoprotein P and glutathione peroxidase 3 were analysed at time of diagnosis. Bulk RNA-sequencing was conducted in matched tumour tissues. Fully adjusted Cox regression models with an interaction term were employed to detect dose-dependent interactions of circulating selenium with the associations of tumour selenoprotein mRNA expression and mortality.
237 deaths were recorded within ~ 9 years follow-up. All three serum selenium biomarkers correlated positively (p < 0.001). All selenoproteins except for GPX6 were expressed in tumour tissues. Single cell RNA-sequencing revealed a heterogeneous expression pattern in the tumour microenvironment. Circulating selenium correlated positively with tumour SELENOW and SELENON expression (p < 0.001). In fully adjusted models, the associations of DIO1, DIO3 and SELENOM with mortality were dose-dependently modified by serum selenium (p < 0.001, p = 0.020, p = 0.038, respectively). With increasing selenium, DIO1 and SELENOM associated with lower, whereas DIO3 expression associated with higher mortality. Association of DIO1 with lower mortality was only apparent in patients with high selenium [above median (70.36 µg/L)], and the HR (95%CI) for one-unit increase in log(FPKM + 1) was 0.70 (0.50-0.98).
This first unbiased analysis of serum selenium with the breast cancer selenotranscriptome identified an effect-modification of selenium on the associations of DIO1, SELENOM, and DIO3 with prognosis. Selenium substitution in patients with DIO1-expressing tumours merits consideration to improve survival.
方法:本研究纳入1453例新诊断乳腺癌患者,这些患者来自多中心前瞻性瑞典癌症组分析网络-乳腺研究。血清总硒,在诊断时分析硒蛋白P和谷胱甘肽过氧化物酶3。在匹配的肿瘤组织中进行大量RNA测序。使用具有相互作用项的完全调整的Cox回归模型来检测循环硒与肿瘤硒蛋白mRNA表达和死亡率的关联的剂量依赖性相互作用。
结果:随访9年内记录了237例死亡。所有三种血清硒生物标志物均呈正相关(p<0.001)。除GPX6外,所有硒蛋白均在肿瘤组织中表达。单细胞RNA测序揭示了肿瘤微环境中的异质表达模式。循环硒与肿瘤SELENOW和SELENON表达呈正相关(p<0.001)。在完全调整的模型中,血清硒剂量依赖性地改变了DIO1,DIO3和SELENOM与死亡率的相关性(分别为p<0.001,p=0.020,p=0.038).随着硒的增加,DIO1和SELENOM关联较低,而DIO3的表达与较高的死亡率相关。DIO1与较低死亡率的关联仅在高硒[高于中位数(70.36µg/L)]的患者中明显,对数增加一个单位(FPKM+1)的HR(95CI)为0.70(0.50-0.98)。
结论:对血清硒与乳腺癌硒转录组的首次无偏分析确定了硒对DIO1,SELENOM,和DIO3与预后。DIO1表达肿瘤患者的硒替代值得考虑提高生存率。