Matched analysis of circulating selenium with the breast cancer selenotranscriptome: a multicentre prospective study

Kamil Demircan, Ylva Bengtsson, Thilo Samson Chillon, Johan Vallon-Christersson, Qian Sun, Christer Larsson, Martin Malmberg, Lao H Saal, Lisa Rydén, Åke Borg, Jonas Manjer, Lutz Schomburg, Kamil Demircan, Ylva Bengtsson, Thilo Samson Chillon, Johan Vallon-Christersson, Qian Sun, Christer Larsson, Martin Malmberg, Lao H Saal, Lisa Rydén, Åke Borg, Jonas Manjer, Lutz Schomburg

Abstract

Introduction: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Glutathione peroxidase; Prognosis; SELENOP; Selenoproteins; Thyroid hormones.

Conflict of interest statement

LS holds shares of selenOmed GmbH, a company involved in selenium status measurement. The remaining authors have no competing interests to declare.

© 2023. BioMed Central Ltd., part of Springer Nature.

Figures

Fig. 1
Fig. 1
 A Study scheme. B Gene expression of selenoproteins in tumour samples of 1453 patients. C Spearman’s correlation matrix of tumour gene expression of selenoprotein genes and circulating selenium biomarker concentrations. D Spearman’s correlation of serum biomarkers with each other and serum biomarkers with SELENOW expression in the tumour. E Single cell RNA-expression of selenoprotein genes in different cells in breast cancer
Fig. 2
Fig. 2
 A Analysis scheme. B Cox regression models in the whole cohort and in low and high selenium subsets, divided according to median selenium concentration of the cohort, i.e. 70.36 µg/L. All models were adjusted for age, tumour size, histological grade, lymph node involvement, expression of HER2/ER/PGR-Receptor, laterality of the tumour, and histological type. P for interaction was tested by adding an interaction term between serum selenium and the gene of interest, marked by purple asterisk
Fig. 3
Fig. 3
 A Contour plot of the interaction between DIO1 expression and serum selenium concentrations on mortality. B Cox regression models depicting the association of DIO1 expression with mortality according to 10th, 50th and 90th quantiles of circulating selenium. C Contour plot of the interaction between DIO3 expression and serum selenium concentrations on mortality. D Cox regression models depicting the association of DIO3 expression with mortality according to 10th, 50th and 90th quantiles of circulating selenium. E Contour plot of the interaction between SELENOM expression and serum selenium concentrations on mortality. F Cox regression models depicting the association of SELENOM expression with mortality according to 10th, 50th and 90th quantiles of circulating selenium. All models were adjusted for age, tumour size, histological grade, lymph node involvement, expression of HER2/ER/PGR-Receptor, laterality of the tumour, and histological type

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