title: Distinct genetic profiles of extracranial and intracranial acral melanoma metastases.
abstract: BACKGROUND
  There is limited knowledge of the genetic alterations in acral melanoma metastases at different anatomic sites. Here, we characterized the genetic abnormalities of metastases in a 51-year-old man with stage IIIC heel melanoma who developed concomitant brain and cutaneous metastases in spite of multiple treatment modalities.
  
  
  METHODS
  Melanoma cells were isolated following palliative resection of the patient's cortical tumor and biopsy of cutaneous thigh metastasis. Mutational analysis using polymerase chain reaction amplification and BLAST, as well as exome sequencing (160 Mb coverage) was performed on the tumors, cell lines generated thereof and normal lymph nodes.
  
  
  RESULTS
  All specimens had neuroblastoma RAS viral oncogene homolog Q61K mutations. There was a 40-fold higher somatic mutation frequency in the brain metastasis compared to the cutaneous metastasis. The former showed truncations of DNA mismatch repair genes (MLH1 and MSH2), and non-canonical BRAF (v-raf murine sarcoma viral oncogene homolog B1), PIK3CA and NF-1 mutations not observed in the extracranial lesion. Genomic profiling of each cell line was concordant with the respective original tumor tissue.
  
  
  CONCLUSIONS
  We present the mutational differences between brain and cutaneous acral melanoma metastases in a patient with concomitant lesions. Further genetic and functional studies are needed to understand the biology of metastatic disease appearing at different sites.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Program of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
authors.affiliation: Program of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: William M
authors.initials: WM
authors.lastname: Lin
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Amin-Mansour
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
authors.forename: Judit
authors.initials: J
authors.lastname: Jané-Valbuena
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.
authors.forename: Levi
authors.initials: L
authors.lastname: Garraway
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Wendi
authors.initials: W
authors.lastname: Bao
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA. chyoon@partners.org.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Yoon
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
mesh_terms: D001706:Biopsy; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D009362:Neoplasm Metastasis; D025542:Neurofibromin 1 / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: C501486:MLH1 protein, human; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras)
keywords: NRAS; acral melanoma; brain metastases; cutaneous metastases; mismatch repair genes