title: Molecular characterization and patient outcome of melanoma nodal metastases and an unknown primary site.
abstract: BACKGROUND
  Melanoma of unknown primary site (MUP) is not a completely understood entity with nodal metastases as the most common first clinical manifestation. The aim of this multicentric study was to assess frequency and type of oncogenic BRAF/NRAS/KIT mutations in MUP with clinically detected nodal metastases in relation to clinicopathologic features and outcome.
  
  
  METHODS
  We analyzed series of 103 MUP patients (period: 1992-2010) after therapeutic lymphadenectomy (LND): 40 axillary, 47 groin, 16 cervical, none treated with BRAF inhibitors. We performed molecular characterization of BRAF/NRAS/KIT mutational status in nodal metastases using direct sequencing of respective coding sequences. Median follow-up time was 53 months.
  
  
  RESULTS
  BRAF mutations were detected in 55 cases (53 %) (51 V600E, 93 %; 4 others, 7 %), and mutually exclusive NRAS mutations were found in 14 cases (14 %) (7 p.Q61R, 4 p.Q61K, 2 p.Q61H, 1 p.Q13R). We have not detected any mutations in KIT. The 5-year overall survival (OS) was 34 %; median was 24 months. We have not found significant correlation between mutational status (BRAF/NRAS) and OS; however, for BRAF or NRAS mutated melanomas we observed significantly shorter disease-free survival (DFS) when compared with wild-type melanoma patients (p = .04; 5-year DFS, 18 vs 19 vs 31 %, respectively). The most important factor influencing OS was number of metastatic lymph nodes >1 (p = .03).
  
  
  CONCLUSIONS
  Our large study on molecular characterization of MUP with nodal metastases showed that MUPs had molecular features similar to sporadic non-chronic-sun-damaged melanomas. BRAF/NRAS mutational status had negative impact on DFS in this group of patients. These observations might have potential implication for molecular-targeted therapy in MUPs.
authors.affiliation: Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Gos
authors.forename: Monika
authors.initials: M
authors.lastname: Jurkowska
authors.forename: Alexander
authors.initials: A
authors.lastname: van Akkooi
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.forename: Hanna
authors.initials: H
authors.lastname: Kosela-Paterczyk
authors.forename: Senada
authors.initials: S
authors.lastname: Koljenović
authors.forename: Nyam
authors.initials: N
authors.lastname: Kamsukom
authors.forename: Wanda
authors.initials: W
authors.lastname: Michej
authors.forename: Arkadiusz
authors.initials: A
authors.lastname: Jeziorski
authors.forename: Piotr
authors.initials: P
authors.lastname: Pluta
authors.forename: Cornelis
authors.initials: C
authors.lastname: Verhoef
authors.forename: Janusz A
authors.initials: JA
authors.lastname: Siedlecki
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008197:Lymph Node Excision; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D009382:Neoplasms, Unknown Primary / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human