Low Protein Expression of both ATRX and ZNRF3 as Novel Negative Prognostic Markers of Adult Adrenocortical Carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare malignancy that is associated with a dismal prognosis. Pan-genomic studies have demonstrated the involvement of ATRX and ZNRF3 genes in adrenocortical tumorigenesis. Our aims were to evaluate the protein expression of ATRX and ZNRF3 in a cohort of 82 adults with ACC and to establish their prognostic value. Two pathologists analyzed immuno-stained slides of a tissue microarray. The low protein expression of ATRX and ZNRF3 was associated with a decrease in overall survival (OS) (p = 0.045, p = 0.012, respectively). The Cox regression for ATRX protein expression of >1.5 showed a hazard ratio (HR) for OS of 0.521 (95% CI 0.273–0.997; p = 0.049) when compared with ≤1.5; for ZNRF3 expression >2, the HR for OS was 0.441 (95% CI, 0.229–0.852; p = 0.015) when compared with ≤2. High ATRX and ZNRF3 protein expressions were associated with optimistic recurrence-free survival (RFS) (p = 0.027 and p = 0.005, respectively). The Cox regression of RFS showed an HR of 0.332 (95%CI, 0.111–0.932) for ATRX expression >2.7 (p = 0.037), and an HR of 0.333 (95%CI, 0.140–0.790) for ZNRF3 expression >2 (p = 0.013). In conclusion, low protein expression of ATRX and ZNRF3 are negative prognostic markers of ACC; however, different cohorts should be evaluated to validate these findings.

Overview of the 2022 WHO Classification of Adrenal Cortical Tumors

“…Global loss of DAXX and/or ATRX expression (Fig. 35 ) may also be identified in ACCs, and this has shown to have prognostic value [ 18 , 120 , 136 ]. The application of MMR proteins (MLH1, MSH2, MSH6 and PMS2) has gained popularity not only for the purpose of screening for an extra-colonic manifestation of Lynch syndrome [ 18 , 179 , 180 ] (Fig.…”

Overexpression of SKA Complex Is Associated With Poor Prognosis in Gliomas

“…In previous studies, several biomarkers associated with poor prognosis have been identified. Among them, eight potential biomarkers were selected from the GEPIA database: DLGAP5, SF1, NEK2, H2AX, PBK, PTEN, ATRX, and DAXX (34,39,(43)(44)(45)(46)(47). DLGAP5 has a unique function in stabilizing spindle formation, and it is strongly expressed during all phases of mitosis.…”

CENPF/CDK1 signaling pathway enhances the progression of adrenocortical carcinoma by regulating the G2/M-phase cell cycle

“…Sbiera et al proposed that SOAT1 may serve as molecular target of mitotane in ACC [ 9 ]. Accumulative literatures have demonstrated that inhibition of WNT–β-catenin signaling pathway [ 10 ], cell-cycle progression through down-regulation of p53–RB [ 11 ], defects in mismatch repair related enzymes (dMMR) [ 12 ], DNA methylation [ 13 ], and abnormal maintenance of telomere (ATRX [ 14 , 15 ], DAX [ 16 ] and TERT [ 8 , 17 ]), were closely bound up with the deterioration and poor prognosis of ACC. In addition, the unique feature of ACC is steroid differentiation, which has been viewed as a potential therapeutic target.…”