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Uveal melanoma driver mutations in GNAQ /11 yield numerous changes in melanocyte biology
Author(s) -
Perez Dahlia E.,
Henle Andrea M.,
Amsterdam Adam,
Hagen Hannah R.,
Lees Jacqueline A.
Publication year - 2018
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12700
Subject(s) - gnaq , melanocyte , melanoma , microphthalmia associated transcription factor , biology , cancer research , phenocopy , mutant , melanin , zebrafish , mutation , microbiology and biotechnology , genetics , gene , transcription factor
Summary Uveal melanoma ( UM ) is the most common primary intraocular cancer and has a high incidence of metastasis, which lacks any effective treatment. Here, we present zebrafish models of UM , which are driven by melanocyte‐specific expression of activating GNAQ or GNA 11 alleles , GNAQ /11 Q209L , the predominant initiating mutations for human UM . When combined with mutant tp53 , GNAQ /11 Q209L transgenics develop various melanocytic tumors, including UM , with near complete penetrance. These tumors display nuclear YAP localization and thus phenocopy human UM . We show that GNAQ /11 Q209L expression induces profound melanocyte defects independent of tp53 mutation, which are apparent within 3 days of development. First, increases in melanocyte number, melanin content, and subcellular melanin distribution result in hyperpigmentation. Additionally, altered melanocyte migration, survival properties, and evasion of normal boundary cues lead to aberrant melanocyte localization and stripe patterning. Collectively, these data show that GNAQ /11 Q209L is sufficient to induce numerous protumorigenic changes within melanocytes.