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

ContextAdrenocortical 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 geneTP53and 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.ObjectiveTo identify new molecular actors driving adrenal tumorigenesis.Experimental designAnalysis 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.ResultsFour mutations were identified, two previously known β-catenin mutations and one alteration in two other genes:JAK3and retinoblastoma gene (RB1). TheJAK3alteration was found in leukocyte DNA and therefore considered as a polymorphism and not a somatic event. The fullRB1tumor 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 inactivatingRB1mutation. Among the seven pRb-negative ACCs, five had an allele loss at theRB1locus.ConclusionsParallel analysis of somatic mutations among known cancer genes allowed us to identifyRB1as a new actor in aggressive ACCs. These results suggest a prognostic significance of pRb expression loss in ACCs.