title: Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14 ARF and RARβ signaling.
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 β (RARB) and CDKN2A alterations affecting p14(ARF) (P < 0.0001), suggesting a functional link between RARβ 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 RARβ. 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 RARβ-p14(ARF) signaling axis, independent of p16(INK4A) and p53 status.
  
  
  CONCLUSIONS
  These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RARβ and p14(ARF) with potential implications for melanoma treatment.
authors.affiliation: Danish Cancer Society Research Center, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. perg@cancer.dk.
authors.forename: Christina
authors.initials: C
authors.lastname: Dahl
authors.forename: Claus
authors.initials: C
authors.lastname: Christensen
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Anders
authors.initials: A
authors.lastname: Lorentzen
authors.forename: Mette Louise
authors.initials: ML
authors.lastname: Skjødt
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.forename: Per
authors.initials: P
authors.lastname: Guldberg
mesh_terms: D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*
chemical_list: D018168:Receptors, Retinoic Acid; D025803:Tumor Suppressor Protein p14ARF; C082925:retinoic acid receptor beta; D014212:Tretinoin