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

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.