Integrative genome comparison of primary and metastatic melanomas Journal Article
| Authors: | Kabbarah, O.; Nogueira, C.; Feng, B.; Nazarian, R. M.; Bosenberg, M.; Wu, M.; Scott, K. L.; Kwong, L. N.; Xiao, Y.; Cordon-Cardo, C.; Granter, S. R.; Ramaswamy, S.; Golub, T.; Duncan, L. M.; Wagner, S. N.; Brennan, C.; Chin, L. |
| Article Title: | Integrative genome comparison of primary and metastatic melanomas |
| Abstract: | A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progressionassociated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes. © 2010 Kabbarah et al. |
| Keywords: | controlled study; human tissue; protein expression; primary tumor; unclassified drug; human cell; gene deletion; genetics; disease course; cancer growth; comparative study; recurrent cancer; lymph node metastasis; metabolism; gene overexpression; melanoma; metastasis; gene amplification; skin neoplasms; genetic association; in vitro study; pathology; survivin; cancer invasion; gene expression regulation; genome analysis; gene expression regulation, neoplastic; skin tumor; gene rearrangement; microarray analysis; disease progression; human genome; nucleotide sequence; tumor protein; neoplasm metastasis; melanoma cell; genomics; neoplasm invasiveness; replication factor a; gene dosage; comparative genomic hybridization; cell invasion; phosphoprotein; genome, human; scatter factor receptor; gene activity; protein kinase c alpha; genetic correlation; copy number variation; microtubule-associated proteins; microtubule associated protein; a kinase anchor protein 9; asp like microcephaly associated protein; cyclic amp dependent protein kinase anchoring protein; replication protein a3; src family associated phosphoprotein 2; birc5 protein, human |
| Journal Title: | PLoS ONE |
| Volume: | 5 |
| Issue: | 5 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2010-05-24 |
| Start Page: | e10770 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0010770 |
| PUBMED: | 20520718 |
| PROVIDER: | scopus |
| PMCID: | PMC2875381 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 20 April 2011" - "Art. No.: e10770" - "Source: Scopus" |
