title: The stable traits of melanoma genetics: an alternate approach to target discovery.
abstract: BACKGROUND
  The weight that gene copy number plays in transcription remains controversial; although in specific cases gene expression correlates with copy number, the relationship cannot be inferred at the global level. We hypothesized that genes steadily expressed by 15 melanoma cell lines (CMs) and their parental tissues (TMs) should be critical for oncogenesis and their expression most frequently influenced by their respective copy number.
  
  
  RESULTS
  Functional interpretation of 3,030 transcripts concordantly expressed (Pearson's correlation coefficient p-value < 0.05) by CMs and TMs confirmed an enrichment of functions crucial to oncogenesis. Among them, 968 were expressed according to the transcriptional efficiency predicted by copy number analysis (Pearson's correlation coefficient p-value < 0.05). We named these genes, "genomic delegates" as they represent at the transcriptional level the genetic footprint of individual cancers. We then tested whether the genes could categorize 112 melanoma metastases. Two divergent phenotypes were observed: one with prevalent expression of cancer testis antigens, enhanced cyclin activity, WNT signaling, and a Th17 immune phenotype (Class A). This phenotype expressed, therefore, transcripts previously associated to more aggressive cancer. The second class (B) prevalently expressed genes associated with melanoma signaling including MITF, melanoma differentiation antigens, and displayed a Th1 immune phenotype associated with better prognosis and likelihood to respond to immunotherapy. An intermediate third class (C) was further identified. The three phenotypes were confirmed by unsupervised principal component analysis.
  
  
  CONCLUSIONS
  This study suggests that clinically relevant phenotypes of melanoma can be retraced to stable oncogenic properties of cancer cells linked to their genetic back bone, and offers a roadmap for uncovering novel targets for tailored anti-cancer therapy.
authors.affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spivey
authors.forename: Valeria
authors.initials: V
authors.lastname: De Giorgi
authors.forename: Yingdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Davide
authors.initials: D
authors.lastname: Bedognetti
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Pos
authors.forename: Qiuzhen
authors.initials: Q
authors.lastname: Liu
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.forename: Maria Libera
authors.initials: ML
authors.lastname: Ascierto
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Uccellini
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reinboth
authors.forename: Lotfi
authors.initials: L
authors.lastname: Chouchane
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D045744:Cell Line, Tumor; D018628:Gene Dosage / Q000235:genetics; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D012333:RNA, Messenger