The stable traits of melanoma genetics: an alternate approach to target discovery
1 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
2 Clinical Research Training Program (CRTP), National Institutes of Health, Bethesda, MD 20892, USA
3 Rush University Medical Center, Rush Medical College, Chicago, IL 60612, USA
4 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
5 Department of Internal Medicine (DiMI), University of Genoa, Viale Benedetto XV,6, 16132 Genoa, Italy
6 Department of Oncology, Biology and Genetics and National Cancer Research Institute of Genoa, Genoa, Italy
7 Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest H-1089, Hungary
8 Department of Oncology, University of Pisa, Pisa, Italy
9 Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy
10 Weill Cornell Medical College in Qatar, Education City, P.O. Box 24144, Doha, Qatar
11 Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA
12 Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Milan, Italy
13 Genelux Corporation, San Diego Science Center, San Diego, CA, USA
14 Department of Biochemistry, Biocenter, University of Würzburg, D-97074 Würzburg, Germany
15 Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and Center for Human Immunology (CHI), National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA
BMC Genomics 2012, 13:156 doi:10.1186/1471-2164-13-156Published: 26 April 2012
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.
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.
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.