American Association for Cancer Research
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Supplementary Table 3 from Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14ARF and RARβ Signaling

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posted on 2023-04-03, 16:06 authored by Christina Dahl, Claus Christensen, Göran Jönsson, Anders Lorentzen, Mette Louise Skjødt, Åke Borg, Graham Pawelec, Per Guldberg

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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 p16INK4A-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 p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14ARF in primary human melanocytes and the steady-state levels of p14ARF in these cells were shown to be regulated via RARβ. Furthermore, the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF signaling axis, independent of p16INK4A 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 RARβ and p14ARF with potential implications for melanoma treatment. Mol Cancer Res; 11(10); 1166–78. ©2013 AACR.

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