title: Mass-array screening of frequent mutations in cancers reveals RB1 alterations in aggressive adrenocortical carcinomas.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assié
authors.forename: Frédérique
authors.initials: F
authors.lastname: Tissier
authors.forename: Olivia
authors.initials: O
authors.lastname: Barreau
authors.forename: Claude
authors.initials: C
authors.lastname: Houdayer
authors.forename: Karine
authors.initials: K
authors.lastname: Perlemoine
authors.forename: Anne
authors.initials: A
authors.lastname: Audebourg
authors.forename: Eric
authors.initials: E
authors.lastname: Clauser
authors.forename: Fernande
authors.initials: F
authors.lastname: René-Corail
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Bertrand
authors.initials: B
authors.lastname: Dousset
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics; D009154:Mutation; D000090063:Proto-Oncogene Mas; D016160:Retinoblastoma Protein / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C507933:JAK3 protein, human; D053616:Janus Kinase 3