Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma.
Systematic analyses of cancer genomes promise to unveil patterns of genetic alterations linked to the genesis and spread of human cancers. High-density single-nucleotide polymorphism (SNP) arrays enable detailed and genome-wide identification of both loss-of-heterozygosity events and copy-number alterations in cancer. Here, by integrating SNP array-based genetic maps with gene expression signatures derived from NCI60 cell lines, we identified the melanocyte master regulator MITF (microphthalmia-associated transcription factor) as the target of a novel melanoma amplification. We found that MITF amplification was more prevalent in metastatic disease and correlated with decreased overall patient survival. BRAF mutation and p16 inactivation accompanied MITF amplification in melanoma cell lines. Ectopic MITF expression in conjunction with the BRAF(V600E) mutant transformed primary human melanocytes, and thus MITF can function as a melanoma oncogene. Reduction of MITF activity sensitizes melanoma cells to chemotherapeutic agents. Targeting MITF in combination with BRAF or cyclin-dependent kinase inhibitors may offer a rational therapeutic avenue into melanoma, a highly chemotherapy-resistant neoplasm. Together, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific cancer development and tumour progression.
Department of Medical Oncology, and Melanoma Program in Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.
Levi A
LA
Garraway
Hans R
HR
Widlund
Mark A
MA
Rubin
Gad
G
Getz
Aaron J
AJ
Berger
Sridhar
S
Ramaswamy
Rameen
R
Beroukhim
Danny A
DA
Milner
Scott R
SR
Granter
Jinyan
J
Du
Charles
C
Lee
Stephan N
SN
Wagner
Cheng
C
Li
Todd R
TR
Golub
David L
DL
Rimm
Matthew L
ML
Meyerson
David E
DE
Fisher
William R
WR
Sellers
D045744:Cell Line, Tumor; D019070:Cell Lineage; D002470:Cell Survival; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D005784:Gene Amplification / Q000235:genetics*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051739:Microphthalmia-Associated Transcription Factor; D009857:Oncogenes / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors