title: Longitudinal study of recurrent metastatic melanoma cell lines underscores the individuality of cancer biology.
abstract: Recurrent metastatic melanoma provides a unique opportunity to analyze disease evolution in metastatic cancer. Here, we followed up eight patients with an unusually prolonged history of metastatic melanoma, who developed a total of 26 recurrences over several years. Cell lines derived from each metastasis were analyzed by comparative genomic hybridization and global transcript analysis. We observed that conserved, patient-specific characteristics remain stable in recurrent metastatic melanoma even after years and several recurrences. Differences among individual patients exceeded within-patient lesion variability, both at the DNA copy number (P<0.001) and RNA gene expression level (P<0.001). Conserved patient-specific traits included expression of several cancer/testis antigens and the c-kit proto-oncogene throughout multiple recurrences. Interestingly, subsequent recurrences of different patients did not display consistent or convergent changes toward a more aggressive disease phenotype. Finally, sequential recurrences of the same patient did not descend progressively from each other, as irreversible mutations such as homozygous deletions were frequently not inherited from previous metastases. This study suggests that the late evolution of metastatic melanoma, which markedly turns an indolent disease into a lethal phase, is prone to preserve case-specific traits over multiple recurrences and occurs through a series of random events that do not follow a consistent stepwise process.
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Hungarian Academy of Sciences-Semmelweis University "Lendület" Experimental and Translational Immunomics Research Group, Budapest, Hungary; Department of Genetics, Cell, and Immunobiology, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Pos
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, Maryland, USA; Department of General Surgery, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spivey
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Department of Biomedical Sciences for Health, Universita' degli Studi di Milano, Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Sommariva
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Jinguo
authors.initials: J
authors.lastname: Chen
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Wunderlich
authors.affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Parisi
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar.
authors.forename: Sara
authors.initials: S
authors.lastname: Tomei
authors.affiliation: Department of Biology, Northern Michigan University, Marquette, Michigan, USA.
authors.forename: Ben D
authors.initials: BD
authors.lastname: Ayotte
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Education City, Doha, Qatar.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Malek
authors.affiliation: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Robbins
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.affiliation: Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.affiliation: Weill Cornell Medical College in Qatar, Education City, Doha, Qatar.
authors.forename: Lotfi
authors.initials: L
authors.lastname: Chouchane
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.affiliation: Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA; Research Branch, Sidra Medical and Research Centre, Doha, Qatar. Electronic address: fmarincola@sidra.org.
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D045744:Cell Line, Tumor; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018450:Disease Progression; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D008137:Longitudinal Studies; D008545:Melanoma / Q000235:genetics* / Q000556:secondary*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D000090063:Proto-Oncogene Mas; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D059467:Transcriptome