Colorectal cancer mortality is associated with low selenoprotein P status at diagnosis

Selenium (Se) deficiency, affecting hundreds of millions of individuals worldwide, is linked to increased incidence of colorectal cancer (CRC), yet tumors paradoxically accumulate Se to evade ferroptosis and promote metastasis. Therefore, understanding the prognostic impact of Se status at diagnosis is crucial to consider and enable personalized interventions. Four Se markers, namely total-Se, the circulating selenoproteins GPx3 and SELENOP, and autoantibodies to SELENOP, were analyzed in participants of the ongoing Colorectal Cancer Study of Austria (CORSA). Final analyses included 519 participants (n = 153 tumor-free, n = 255 adenoma and n = 111 CRC). Subjects were enrolled following a positive fecal immunochemical test, underwent a colonoscopy for diagnosis, and were followed up for 15 years. Total-Se concentration and GPx3 activity did not differ across groups, but SELENOP concentrations were lower in CRC (median (IQR); controls: 2.9 (0.9), adenoma: 2.8 (1.0), CRC: 2.4 (0.9); p < 0.001). Prevalence of SELENOP autoimmunity was <1 % in controls, but >5 % in patients. Total Se and SELENOP levels above the median were associated with better survival in all groups. SELENOP displayed an inverse association with mortality in fully adjusted models (HR(CI) per SD for SELENOP; controls: 0.62(0.46-0.83), adenomas: 0.73 (0.59-0.90), CRC: 0.64(0.49-0.84)). Adding any Se biomarker, particularly SELENOP, to a model with established clinical parameters improved prognostication, and the highest prognostic values were observed when including SELENOP or all three Se biomarkers. Data-driven clustering analysis identified three distinct clusters based on Se markers, one of which displayed a remarkably increased risk for mortality (HR; 1.8). We conclude that SELENOP deficiency at the time of diagnosis is inversely associated with mortality risk and improves prognostication over clinical parameters. As selenoprotein expression is a modifiable parameter mainly dependent on selenium intake, the personalized correction of a diagnosed deficiency should be investigated in future studies to improve CRC patient survival.