Integrative genome comparison of primary and metastatic melanomas.
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 progression-associated 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.
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Omar
O
Kabbarah
Cristina
C
Nogueira
Bin
B
Feng
Rosalynn M
RM
Nazarian
Marcus
M
Bosenberg
Min
M
Wu
Kenneth L
KL
Scott
Lawrence N
LN
Kwong
Yonghong
Y
Xiao
Carlos
C
Cordon-Cardo
Scott R
SR
Granter
Sridhar
S
Ramaswamy
Todd
T
Golub
Lyn M
LM
Duncan
Stephan N
SN
Wagner
Cameron
C
Brennan
Lynda
L
Chin
D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D005784:Gene Amplification / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology; D000077022:Survivin
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D000077022:Survivin