An oncogenic role for ETV1 in melanoma.
Copy gains involving chromosome 7p represent one of the most common genomic alterations found in melanomas, suggesting the presence of "driver" cancer genes. We identified several tumor samples that harbored focal amplifications situated at the peak of common chromosome 7p gains, in which the minimal common overlapping region spanned the ETV1 oncogene. Fluorescence in situ hybridization analysis revealed copy gains spanning the ETV1 locus in >40% of cases, with ETV1 amplification (>6 copies/cell) present in 13% of primary and 18% of metastatic melanomas. Melanoma cell lines, including those with ETV1 amplification, exhibited dependency on ETV1 expression for proliferation and anchorage-independent growth. Moreover, overexpression of ETV1 in combination with oncogenic NRAS(G12D) transformed primary melanocytes and promoted tumor formation in mice. ETV1 overexpression elevated microphthalmia-associated transcription factor expression in immortalized melanocytes, which was necessary for ETV1-dependent oncogenicity. These observations implicate deregulated ETV1 in melanoma genesis and suggest a pivotal lineage dependency mediated by oncogenic ETS transcription factors in this malignancy.
Jané-Valbuena
Judit
J
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Widlund
Hans R
HR
Perner
Sven
S
Johnson
Laura A
LA
Dibner
Aurora C
AC
Lin
William M
WM
Baker
Alissa C
AC
Nazarian
Rosalynn M
RM
Vijayendran
Krishna G
KG
Sellers
William R
WR
Hahn
William C
WC
Duncan
Lyn M
LM
Rubin
Mark A
MA
Fisher
David E
DE
Garraway
Levi A
LA
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D005784:Gene Amplification; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D051739:Microphthalmia-Associated Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf