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Abstract：
Low serum selenium and altered tumour RNA expression of certain selenoproteins are associated with a poor breast cancer prognosis. Selenoprotein expression stringently depends on selenium availability, hence circulating selenium may interact with tumour selenoprotein expression. However, there is no matched analysis to date.
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.
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.
摘要：
背景：低血清硒和某些硒蛋白的肿瘤RNA表达改变与乳腺癌预后不良相关。硒蛋白的表达严格取决于硒的可用性，因此循环硒可能与肿瘤硒蛋白表达相互作用。然而,到目前为止还没有匹配的分析。
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。
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。
