Early Postoperative Circulating miR-483-5p Is a Prognosis Marker for Adrenocortical Cancer

Abstract

We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5% sensitivity (CI 31.6-86.1) and 100% specificity (CI 71.5-100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.

The Role of Biomarkers in Adrenocortical Carcinoma: A Review of Current Evidence and Future Perspectives

“…High circulating levels of miR-483-5p or low circulating levels of miR-195 are associated with both shorter recurrence-free survival and shorter overall survival in ACC [ 184 ]. Serum miR-483-5p levels measured 3 months after surgical procedure were, for example, higher in those with recurrence disease or lethal outcome within three years than in those without [ 185 ]. Receiver operating characteristic analysis showed that a value of 752,898 copies/mL was a cut off value to prognosticate recurrence with 61.5% sensitivity and 100% specificity [ 185 ].…”

“…Serum miR-483-5p levels measured 3 months after surgical procedure were, for example, higher in those with recurrence disease or lethal outcome within three years than in those without [ 185 ]. Receiver operating characteristic analysis showed that a value of 752,898 copies/mL was a cut off value to prognosticate recurrence with 61.5% sensitivity and 100% specificity [ 185 ]. Beside circulating miR-483-5p, its urinary counterpart has been evaluated in patients with adrenal tumors [ 186 ].…”

“…Tumor-specific mutations were found in the cfDNA of one of the three patients who had metastatic ACC at diagnosis. The preoperative cfDNA showed the same mutations as by NGS, both pre- and postoperative, but in the latter with lower frequencies [ 185 ]. Furthermore, ctDNA, i.e., fragments of DNA released directly by tumor cells into the blood stream is discriminated from other non-tumoral cf-DNA by the detection of somatic mutations, specific of cancer cells, tumor type and stage [ 190 ].…”

Current Status and Future Targeted Therapy in Adrenocortical Cancer

“…Confirming the previously reported data ( 42 – 44 ), MIR483 , located on intron 2 of the IGF2 locus, is overexpressed in ACC. Interestingly, a recent single-institution study of 48 patients suggested that mIR-483-5p measured after initial surgery for ACC can be a potential early post-operative biomarker for ACC prognosis to predict recurrence-free survival ( 45 ). In the ENSAT cohort, miRNA analysis revealed the upregulation of 11 miRNAs belonging to the miRNA-506-514 cluster (Xq27.3) and downregulation of 38 miRNAs to the imprinted DLK1-MEG3 cluster (14q32.2).…”

Adrenocortical Carcinoma

“…Four articles report the results of explorative studies on the prognostic role of the counts of two tissue markers: sterol-O-acyl transferase 1 (SOAT1) [ 10 ] and CD8+-cytotoxic T lymphocyte [ 11 ], the latter being assessed in a pediatric series. Two blood parameters were also assessed in the form of circulating tumor cells [ 12 ] and miR-483-5p [ 13 ]. Another paper showed that a pervasive circulating autoantibody response against the cancer testis antigen FATE1—which is detected both in pediatric and adult ACC patients—is negatively correlated to disease-free survival (DFS) and overall survival (OS) in adult patients and is associated with decreased immune response-associated gene expression [ 14 ].…”