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 abnormalalterations 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 andDNA 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.
| Original language | English |
|---|---|
| Pages (from-to) | 128-141 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 4 |
| Issue number | 1 |
| State | Published - 2013 |
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All Science Journal Classification (ASJC) codes
- Oncology
Cite this
Altered transcriptome signature of phenotypically normal skin fibroblasts heterozygous for CDKN2A in familial melanoma : Relevance to early intervention. / Fan, Meiyun; Pfeffer, Susan R.; Lynch, Henry T.; Cassidy, Pamela; Leachman, Sancy; Pfeffer, Lawrence M.; Kopelovich, Levy.
In: Oncotarget, Vol. 4, No. 1, 2013, p. 128-141.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Altered transcriptome signature of phenotypically normal skin fibroblasts heterozygous for CDKN2A in familial melanoma
T2 - Relevance to early intervention
AU - Fan, Meiyun
AU - Pfeffer, Susan R.
AU - Lynch, Henry T.
AU - Cassidy, Pamela
AU - Leachman, Sancy
AU - Pfeffer, Lawrence M.
AU - Kopelovich, Levy
PY - 2013
Y1 - 2013
N2 - 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 abnormalalterations 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 andDNA 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.
AB - 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 abnormalalterations 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 andDNA 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.
UR - http://www.scopus.com/inward/record.url?scp=84875797484&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875797484&partnerID=8YFLogxK
M3 - Article
C2 - 23371019
AN - SCOPUS:84875797484
VL - 4
SP - 128
EP - 141
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 1
ER -