Mass-array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas

Abstract

Context : Adrenocortical carcinoma (ACC) is a rare disease with a poor overall outcome. Transcriptome analysis identified two groups of ACCs with different prognosis. In aggressive ACCs, somatic mutations of the tumor suppressor gene TP53 and the proto-oncogene β-catenin are detected in 50% of cases. For the remaining aggressive ACCs and for the group with a better prognosis, molecular alterations are unknown. Objective: To identify new molecular actors driving adrenal tumorigenesis. Experimental design: Analysis by mass array of 374 mutations among 32 common oncogenes or tumor suppressor genes was performed on the tumoral DNA of 26 ACCs, using Sequenom OncoCarta Panels. Results: Four mutations were identified, two previously known β-catenin mutations and one alteration in two other genes: JAK3 and retinoblastoma gene (RB1). The JAK3 alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The full RB1 tumor suppressor gene was subsequently sequenced in a cohort of 49 ACCs (26 ACCs from the 'OncoCarta cohort' and 23 other ACCs): three somatic mutations were identified, all in the poor-outcome ACC group. By immunohistochemistry, a loss of the retinoblastoma protein (pRb) was found exclusively in aggressive ACCs in 27% of cases (seven out of 26), three of them with an inactivating RB1 mutation. Among the seven pRb-negative ACCs, five had an allele loss at the RB1 locus. Conclusions: Parallel analysis of somatic mutations among known cancer genes allowed us to identify RB1 as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs. © 2014 European Society of Endocrinology.