LAUSR

Simple Summary Adrenocortical carcinoma (ACC) is a rare but aggressive cancer with a high rate of fatality. Accurate prediction of cancer relapse following therapy and prognosis (fatality) is essential to improve patient management. This research aims to significantly increase this prediction capacity. We produced four multigene sets: Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B. These panels have not been studied in ACC and are thus novel. Importantly, they predict ACC’s relapse and death risk with impressively high levels of accuracy. At the disease level, these multigene panels are associated with critical ACC factors, including TP53 gene mutation and changes in immunological processes. Furthermore, we discovered a new ACC factor in predicting ACC relapse and fatality: mesenchymal stem cells (MSCs). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B all strongly correlate with MSCs. Collectively, the identification of MSC association with ACC advances our understanding of ACC; Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B possess significant potential in improving ACC management. Abstract Effective assessment of adrenocortical carcinoma (ACC) prognosis is critical in patient management. We report four novel and robust prognostic multigene panels. Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B predict ACC relapse at area under the curve (AUC) of 0.89, 0.79, 0.78, and 0.80, respectively, and fatality at AUC of 0.91, 0.88, 0.85, and 0.87, respectively. Among their 33 component genes, 31 are novel. They could be differentially expressed in ACCs from normal tissues, tumors with different severity (stages and lymph node metastasis), ACCs with TP53 mutations, and tumors with differentially expressed immune checkpoints (CTLA4, PD1, TGFBR1, and others). All panels correlate with reductions of ACC-associated CD8+ and/or NK cells. Furthermore, we provide the first evidence for the association of mesenchymal stem cells (MSCs) with ACC relapse (p = 2 × 10−6) and prognosis (p = 2 × 10−8). Sig27var25, SigIQvar8, SigCmbnvar5, and SigCmbn_B correlate with MSC (spearman r ≥ 0.53, p ≤ 1.38 × 10−5). Sig27var25 and SigIQvar8 were derived from a prostate cancer (PC) and clear cell renal cell carcinoma (ccRCC) multigene signature, respectively; SigCmbnvar5 and SigCmbn_B are combinations of both panels, revealing close relationships of ACC with PC and ccRCC. The origin of these four panels from PC and ccRCC favors their prognostic potential towards ACC.