In vitro behavior and UV response of melanocytes derived from carriers of CDKN2A mutations and MC1R variants
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 05, 2018
- Source ID
- 10.1111/pcmr.12732
Entities
People
- Ana Luisa Kadekaro
- Ayesha Anwar
- Barbara Hernando
- Dorothy Bennett
- Kevin Choi
- Pamela Cassidy
- Renny J. Starner
- Sancy Leachman
- Steven Guard
- Viki B. Swope
- Zalfa A. Abdel-Malek
Organizations
- Congressionally Directed Medical Research Programs
- Huntsman Cancer Institute
- National Cancer Institute
- Oregon Health & Science University
- St George's, University of London
- University of Cincinnati