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Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14(ARF) and RAR beta Signaling

Dahl, Christina; Christensen, Claus; Jönsson, Göran B LU ; Lorentzen, Anders; Skjodt, Mette Louise; Borg, Åke LU ; Pawelec, Graham and Guldberg, Per (2013) In Molecular Cancer Research 11(10). p.1166-1178
Abstract
Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16(INK4A)-CDK4-RB, RAS-RAF-MEK-ERK and... (More)
Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16(INK4A)-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor beta (RARB) and CDKN2A alterations affecting p14(ARF) (P < 0.0001), suggesting a functional link between RAR beta signaling and the melanoma-suppressive activities of p14(ARF). Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14(ARF) in primary human melanocytes and the steady-state levels of p14(ARF) in these cells were shown to be regulated via RAR beta. Furthermore, the ability of ATRA to induce senescence is reduced in p14(ARF)-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARb-p14(ARF) signaling axis, independent of p16(INK4A) and p53 status. Implications: These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RAR beta and p14(ARF) with potential implications for melanoma treatment. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
11
issue
10
pages
1166 - 1178
publisher
American Association for Cancer Research
external identifiers
  • wos:000325805000005
  • scopus:84886376886
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-13-0006
language
English
LU publication?
yes
id
bc0f949f-5c69-42ec-93de-0e7bba77175d (old id 4163486)
date added to LUP
2013-12-06 12:27:37
date last changed
2019-03-17 03:54:39
@article{bc0f949f-5c69-42ec-93de-0e7bba77175d,
  abstract     = {Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16(INK4A)-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor beta (RARB) and CDKN2A alterations affecting p14(ARF) (P &lt; 0.0001), suggesting a functional link between RAR beta signaling and the melanoma-suppressive activities of p14(ARF). Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14(ARF) in primary human melanocytes and the steady-state levels of p14(ARF) in these cells were shown to be regulated via RAR beta. Furthermore, the ability of ATRA to induce senescence is reduced in p14(ARF)-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARb-p14(ARF) signaling axis, independent of p16(INK4A) and p53 status. Implications: These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RAR beta and p14(ARF) with potential implications for melanoma treatment.},
  author       = {Dahl, Christina and Christensen, Claus and Jönsson, Göran B and Lorentzen, Anders and Skjodt, Mette Louise and Borg, Åke and Pawelec, Graham and Guldberg, Per},
  issn         = {1557-3125},
  language     = {eng},
  number       = {10},
  pages        = {1166--1178},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Research},
  title        = {Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14(ARF) and RAR beta Signaling},
  url          = {http://dx.doi.org/10.1158/1541-7786.MCR-13-0006},
  volume       = {11},
  year         = {2013},
}