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In vitro behavior and UV response of melanocytes derived from carriers of CDKN 2A mutations and MC 1R variants
Author(s) -
Hernando Barbara,
Swope Viki B.,
Guard Steven,
Starner Renny J.,
Choi Kevin,
Anwar Ayesha,
Cassidy Pamela,
Leachman Sancy,
Kadekaro Ana Luisa,
Bennett Dorothy C.,
AbdelMalek Zalfa A.
Publication year - 2019
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.12732
Subject(s) - biology , mutation , melanocyte , melanocortin 1 receptor , mutant , cancer research , dna damage , allele , cell culture , germline mutation , microbiology and biotechnology , somatic cell , genetics , melanoma , dna , gene
Summary Coinheritance of germline mutation in cyclin‐dependent kinase inhibitor 2A ( CDKN 2A) and loss‐of‐function ( LOF ) melanocortin 1 receptor ( MC 1R ) variants is clinically associated with exaggerated risk for melanoma. To understand the combined impact of these mutations, we established and tested primary human melanocyte cultures from different CDKN 2A mutation carriers, expressing either wild‐type MC 1R or MC 1R LOF variant(s). These cultures expressed the CDKN 2A product p16 ( INK 4A) and functional MC 1R. Except for 32ins24 mutant melanocytes, the remaining cultures showed no detectable aberrations in proliferation or capacity for replicative senescence. Additionally, the latter cultures responded normally to ultraviolet radiation ( UV ) by cell cycle arrest, JNK , p38, and p53 activation, hydrogen peroxide generation, and repair of DNA photoproducts. We propose that malignant transformation of melanocytes expressing CDKN 2A mutation and MC 1R LOF allele(s) requires acquisition of somatic mutations facilitated by MC 1R genotype or aberrant microenvironment due to CDKN 2A mutation in keratinocytes and fibroblasts.