Oncotarget

Research Papers:

Altered transcriptome signature of phenotypically normal skin fibroblasts heterozygous for CDKN2A in familial melanoma: relevance to early intervention

Meiyun Fan, Susan R. Pfeffer, Henry T. Lynch, Pamela Cassidy, Sancy Leachman, Lawrence M. Pfeffer and Levy Kopelovich _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2013; 4:128-141. https://doi.org/10.18632/oncotarget.786

Metrics: PDF 1470 views  |   HTML 2216 views  |   ?  


Abstract

Meiyun Fan1*, Susan R. Pfeffer1*, Henry T. Lynch2, Pamela Cassidy3, Sancy Leachman3, Lawrence M. Pfeffer1, and Levy Kopelovich4

1 Department of Pathology and Laboratory Medicine, and the Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA

2 Department of Preventive Medicine, Creighton University, Omaha, NE, USA

3 Melanoma & Cutaneous Oncology Program, Huntsman Cancer Institute, and Department of Dermatology, University of Utah, Salt Lake City, UT, USA

4 Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA

* Contributed equally to the work

Correspondence:

Levy Kopelovich, email:

Lawrence M. Pfeffer, email:

Keywords: Familial Melanoma/ gene expression/ CDKN2A/ p16/ Mutations/ Melanoma

Received: December 14, 2012, Accepted: January 18, 2013, Published: January 19, 2013

Abstract

Familial melanoma (FM) is a dominantly heritable cancer that is associated with mutations in the tumor suppressor CDKN2A/p16. In FM, a single inherited “hit” occurs in every somatic cell, enabling interrogation of cultured normal skin fibroblasts (SFs) from FM gene carriers as surrogates for the cell of tumor origin, namely the melanocyte. We compared the gene expression profile of SFs from FM individuals with two distinct CDKN2A/p16 mutations (V126D-p16 and R87P-p16) with the gene expression profile of SFs from age-matched individuals without p16 mutations and with no family history of melanoma. We show an altered transcriptome signature in normal SFs bearing a single-hit inherited mutation in the CDKN2A/p16 gene, wherein some of these abnormal alterations recapitulate changes observed in the corresponding cancer. Significantly, the extent of the alterations is mutation-site specific with the R87P-p16 mutation being more disruptive than the V126D-p16 mutation. We also examined changes in gene expression after exposure to ultraviolet (UV) radiation to define potential early biomarkers triggered by sun exposure. UV treatment of SFs from FM families induces distinct alterations in genes related to cell cycle regulation and DNA damage responses that are also reported to be dysregulated in melanoma. Importantly, these changes were diametrically opposed to UV-induced changes in SF from normal controls. We posit that changes identified in the transcriptome of SF from FM mutation carriers represent early events critical for melanoma development. As such, they may serve as specific biomarkers of increased risk as well as molecular targets for personalized prevention strategies in high-risk populations.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 786