title: Complete loss of PTEN protein expression correlates with shorter time to brain metastasis and survival in stage IIIB/C melanoma patients with BRAFV600 mutations.
abstract: OBJECTIVE
  Loss of function of PTEN is a frequent event in melanoma, particularly in tumors with BRAF(V600) mutations. The prevalence, pathologic features, and clinical outcomes associated with PTEN loss in patients with stage IIIB/C melanoma were interrogated to improve our understanding of the clinical significance of this molecular event.
  
  
  METHODS
  Archival tissue from lymphadenectomy specimens among patients (n = 136) with stage IIIB or IIIC melanoma was assessed by DNA sequencing for activating BRAF and NRAS mutations, and by immunohistochemistry for the expression of PTEN protein. Associations of these molecular aberrations with demographics, tumor characteristics, and clinical outcomes were determined.
  
  
  RESULTS
  The prevalence of BRAF(V600) mutations (40% overall), NRAS mutations (10%), and PTEN loss (25%) did not vary by pathologic substage. BRAF/NRAS mutation status did not correlate with distant disease-free survival (DDFS) or overall survival (OS). Complete loss of PTEN expression correlated with shorter OS but not DDFS. When stratified by specific sites of distant metastasis, PTEN loss was associated with significantly shorter time to melanoma brain metastasis (MBM), but not to liver, lung, or bone metastasis. Analysis of PTEN in mutationally defined subsets showed that PTEN loss was significantly associated with OS and time to MBM in patients with BRAF(V600) mutations.
  
  
  CONCLUSIONS
  Loss of PTEN protein expression correlates significantly with decreased OS and time to MBM in stage IIIB/C melanoma patients with BRAF(V600) mutations. The findings add to evidence supporting a significant role for PTEN loss and the PI3K-AKT pathway in melanoma.
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Amanda D
authors.initials: AD
authors.lastname: Bucheit
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alan
authors.initials: A
authors.lastname: Siroy
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael
authors.initials: M
authors.lastname: Tetzlaff
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Denai
authors.initials: D
authors.lastname: Milton
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fox
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roland
authors.initials: R
authors.lastname: Bassett
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
authors.affiliation: Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Gershenwald
authors.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas. mdavies@mdanderson.org.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human