Establishing Adrenocortical Carcinoma Specific Prognostic Genes Signature

Abstract Introduction/Objective Adrenal Cortical Carcinoma (ACC) is a rare malignant neoplasms originating from adrenal cortical tissue with an annual incidence rate of 1 to 2 cases per million individuals. These tumors have poor prognosis with 5-year disease free survival being 30% after complete resection in Stage I to Stage III patients. Hence, there is a need for identifying prognostic markers for effective management of disease in these patients. Methods We analyzed the data in The Cancer Genome Atlas of 1141 ACC individuals, using cbioportal.org, a web- based platform for analysis of large-scale cancer genomics data sets, and derived correlation between prognosis and genetic alterations in approximately 51,309 genes. Results We identified 15 signature genes (NOTCH1, TP53, ZNRF3, LRP1, KIF5A, MDM2, LETMD1, MTOR, NOTCH3, RERE, SMARCC2, LDLR, HRNR, AVPR1A and PCDH15), alterations in which indicated a poor prognosis for ACC individuals. Analysis of 15 signature genes demonstrated that disease specific median survival for the patients with ACC, was reduced to 39.5 months (p value < 8 x 10 -9 and sensitivity of 93%) when any one or more of these genes was altered. Whereas, disease specific median survival was greater than 180 months (90% survival being 180 months) with no alteration in our signature genes. In addition, our analysis of our signature genes demonstrates reduced overall survival, disease free survival and progression free survival in individuals having alterations in our signature genes. Moreover, our set of 15 genes belonged mainly to MDM2-TP53, NOTCH and mTOR pathways, and small molecule modulators of these pathways are in process of development. Conclusion Our 15 gene signature was not only able to predict poor prognosis in ACC, but also has the potential to serve as a molecular marker set for initiation of NOTCH and mTOR specific targeted therapies in these patients.