title: High frequency of submicroscopic hemizygous deletion is a major mechanism of loss of expression of PTEN in uveal melanoma.
abstract: OBJECTIVE
  Although cytogenetic aberrations at 10q have been reported in up to 27% of uveal melanomas, the role of PTEN in the pathogenesis of uveal melanoma is largely unknown. Our aim was to determine the frequency and clinical significance of PTEN alterations in uveal melanomas.
  
  
  METHODS
  We examined PTEN expression using immunohistochemistry in 75 sporadic uveal melanomas, with an average follow-up of 89 months. Molecular cytogenetic alterations were studied using comparative genomic hybridization (CGH). Genotyping was carried out using an intragenic PTEN marker and two flanking markers. Mutational analysis of PTEN was also carried out.
  
  
  RESULTS
  Of the 75 tumors, 12 (16%) showed no PTEN immunostaining, 32 (42.7%) showed weak to moderate staining and the remaining 31 (38.2%) showed staining similar to the normal internal controls. Using CGH, only two (15.4%) of 13 samples showed any loss of 10q. However, in the 38 tumors with informative genotyping, we found that 29 (76.3%) had loss of heterozygosity (LOH) of at least one PTEN marker, and 15 (39.5%) showed LOH of at least two markers. Mutations in the coding region of PTEN were identified in four (11.4%) of 35 tumors. Further, loss of cytoplasmic PTEN expression by immunohistochemistry was associated with shortened disease-free survival (P = .029).
  
  
  CONCLUSIONS
  This is the first demonstration that PTEN is a tumor suppressor involved in uveal melanoma pathogenesis and may be associated with clinical outcome. Our data also suggest that submicroscopic deletion, but not large deletions, is the major mechanism of loss of PTEN expression in uveal melanomas.
authors.affiliation: Department of Ophthalmology, the Ohio State University, Columbus, USA.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Abdel-Rahman
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhou
authors.forename: Elson L
authors.initials: EL
authors.lastname: Craig
authors.forename: Frederick H
authors.initials: FH
authors.lastname: Davidorf
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human