title: Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target.
abstract: OBJECTIVE
  An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches.
  
  
  METHODS
  Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors.
  
  
  RESULTS
  The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases.
  
  
  CONCLUSIONS
  These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors.
authors.affiliation: Departments of Melanoma Medical Oncology, gchen2@mdanderson.org.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Pathology.
authors.forename: Nitin
authors.initials: N
authors.lastname: Chakravarti
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, California; and.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Aardalen
authors.affiliation: Pathology.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Pathology.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
authors.affiliation: Division of Medical Genetics, Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Bradley
authors.initials: B
authors.lastname: Wubbenhorst
authors.affiliation: Systems Biology and.
authors.forename: Sang-Bae
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas;
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.affiliation: Pathology.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Ledoux
authors.affiliation: Departments of Melanoma Medical Oncology.
authors.forename: Y N Vashisht
authors.initials: YN
authors.lastname: Gopal
authors.affiliation: Departments of Melanoma Medical Oncology.
authors.forename: Cristiano Goncalves
authors.initials: CG
authors.lastname: Pereira
authors.affiliation: Departments of Melanoma Medical Oncology.
authors.forename: Wanleng
authors.initials: W
authors.lastname: Deng
authors.affiliation: Systems Biology and.
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Medical Genetics, Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Pathology.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.affiliation: Pathology.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, California; and.
authors.forename: Darrin
authors.initials: D
authors.lastname: Stuart
authors.affiliation: Departments of Melanoma Medical Oncology, Systems Biology and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Davies
mesh_terms: D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology*; D056915:DNA Copy Number Variations / Q000235:genetics; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human