In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants

Barbara Hernando, Viki B. Swope, Steven Guard, Renny J. Starner, Kevin Choi, Ayesha Anwar, Pamela Cassidy, Sancy Leachman, Ana Luisa Kadekaro, Dorothy C. Bennett, Zalfa A. Abdel-Malek

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Coinheritance of germline mutation in cyclin-dependent kinase inhibitor 2A (CDKN2A) and loss-of-function (LOF) melanocortin 1 receptor (MC1R) 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 CDKN2A mutation carriers, expressing either wild-type MC1R or MC1RLOF variant(s). These cultures expressed the CDKN2A product p16 (INK4A) and functional MC1R. 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 CDKN2A mutation and MC1RLOF allele(s) requires acquisition of somatic mutations facilitated by MC1R genotype or aberrant microenvironment due to CDKN2A mutation in keratinocytes and fibroblasts.

Original languageEnglish (US)
Pages (from-to)259-268
Number of pages10
JournalPigment Cell and Melanoma Research
Volume32
Issue number2
DOIs
StatePublished - Mar 1 2019

Keywords

  • CDKN2A
  • MC1R
  • proliferation
  • replicative senescence
  • ultraviolet radiation

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

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    Hernando, B., Swope, V. B., Guard, S., Starner, R. J., Choi, K., Anwar, A., Cassidy, P., Leachman, S., Kadekaro, A. L., Bennett, D. C., & Abdel-Malek, Z. A. (2019). In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants. Pigment Cell and Melanoma Research, 32(2), 259-268. https://doi.org/10.1111/pcmr.12732