Sterol O-Acyl Transferase 1 as a Prognostic Marker of Adrenocortical Carcinoma

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0–4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26–3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09–4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.

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

“…Malignancies develop protector mechanisms for self-survival. Generally, defects are harbored in evolutionarily conserved pathways, such as the Wnt/β-catenin pathway [ 39 ]. However, nine acquired biological capabilities, known as cancer hallmarks, are involved in a multistep tumorigenesis process [ 40 ].…”

“…The occurrence of Wnt/β-catenin signaling has been established in different malignancies [ 37 , 84 , 85 ]. ZNRF3 acts as a tumor suppressor of the Wnt/β-catenin pathway [ 39 , 68 , 69 , 86 , 87 , 88 ]. Tissier et al have already demonstrated the role of Wnt/β-catenin in adrenal tumorigenesis [ 89 ].…”

Adrenocortical Carcinoma: Updates of Clinical and Pathological Features after Renewed World Health Organisation Classification and Pathology Staging

“…In addition, large tumour size and cortisol-secreting tumour were additional factors for ACC-specific death [ 49 ]. Moreover, there are many predictive features proposed for the prognosis of patients with ACC such as mitotic grading [ 52 ], Ki-67 index [ 75 ], mi-RNAs expression [ 76 ], expression of PDL-1 [ 77 ], SF-1 [ 78 ] and sterol-O-acyl transferase 1 (SOAT1) [ 79 ]. Preliminary data also shows that for localised ACC, molecular makers (expression, methylation, and chromosome alterations) could predict cancer recurrence [ 9 ].…”

Prognostic Alternative mRNA Splicing in Adrenocortical Carcinoma

“…Studies of molecular prognostic markers of ACC are limited. Lacombe et al reported sterol-O-acyl transferase 1 as a prognostic marker (41). A simple prognostic marker based on the differential expression of two genes (BUB1B-PINK1) was developed by de Reyniès (42).…”