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Comparative Study
, 5 (6), 1439-51

Capturing the Biological Impact of CDKN2A and MC1R Genes as an Early Predisposing Event in Melanoma and Non Melanoma Skin Cancer

Affiliations
Comparative Study

Capturing the Biological Impact of CDKN2A and MC1R Genes as an Early Predisposing Event in Melanoma and Non Melanoma Skin Cancer

Joan Anton Puig-Butille et al. Oncotarget.

Abstract

Germline mutations in CDKN2A and/or red hair color variants in MC1R genes are associated with an increased susceptibility to develop cutaneous melanoma or non melanoma skin cancer. We studied the impact of the CDKN2A germinal mutation p.G101W and MC1R variants on gene expression and transcription profiles associated with skin cancer. To this end we set-up primary skin cell co-cultures from siblings of melanoma prone-families that were later analyzed using the expression array approach. As a result, we found that 1535 transcripts were deregulated in CDKN2A mutated cells, with over-expression of immunity-related genes (HLA-DPB1, CLEC2B, IFI44, IFI44L, IFI27, IFIT1, IFIT2, SP110 and IFNK) and down-regulation of genes playing a role in the Notch signaling pathway. 3570 transcripts were deregulated in MC1R variant carriers. In particular, genes related to oxidative stress and DNA damage pathways were up-regulated as well as genes associated with neurodegenerative diseases such as Parkinson's, Alzheimer and Huntington. Finally, we observed that the expression signatures indentified in phenotypically normal cells carrying CDKN2A mutations or MC1R variants are maintained in skin cancer tumors (melanoma and squamous cell carcinoma). These results indicate that transcriptome deregulation represents an early event critical for skin cancer development.

Conflict of interest statement

The authors state no conflict of interest.

Figures

Figure 1
Figure 1. Impact of germinal CDKN2A mutation on global transcript profile in melanocyte-keratinocyte co-culture system
Functional classification of the set of 78 of 108 deregulated genes in CDKN2A mutants are indicated in Fig.1a Up-regulated genes and Fig.1b Down-regulated genes. T. Factors (transcription factors), Immune modulation & IFN (Immunomodulation and interferon related genes); Cell. Components and metabolism (Cellular components and metabolism), Diff & Melanogenesis (differentiation and melanogenesis)
Figure 1
Figure 1. Impact of germinal CDKN2A mutation on global transcript profile in melanocyte-keratinocyte co-culture system
Functional classification of the set of 78 of 108 deregulated genes in CDKN2A mutants are indicated in Fig.1a Up-regulated genes and Fig.1b Down-regulated genes. T. Factors (transcription factors), Immune modulation & IFN (Immunomodulation and interferon related genes); Cell. Components and metabolism (Cellular components and metabolism), Diff & Melanogenesis (differentiation and melanogenesis)
Figure 2
Figure 2. Set of immunomodulation and interferon response deregulated in mutant CDKN2A co-cultures
The logarithm of the Fold change (LogFC) for the set of genes is indicated for wild-type MC1R co-cultures (wt_MC1R; green) and for Red Hair Colour MC1R variants co-cultures (RHC_MC1R; yellow).
Figure 3
Figure 3. Deregulated pathways in RHC MC1R melanocyte-keratinocyte co-culture system
In blue are the number of total genes annotated within the pathway, in red are the number of deregulated genes in the RHC MC1R co-cultures. The KEGG term is indicated for each pathway (axis X). * Pathways related to neurodegenerative diseases.
Figure 4
Figure 4. Genes inversely expressed in mutant CDKN2A and RHC MC1R
136 genes were found inversely expressed between mutant CDKN2A and RHC MC1R genes (listed in Table S3). A: RHC MC1R vs wt MC1R (both mutant CDKN2A); B: mutant CDKN2A vs wt CDKN2A (both RHC MC1R); C: mutant CDKN2A vs wt CDKN2A (both wt MC1R); D: RHC MC1R vs wt MC1R (both wt CDKN2A).
Figure 5
Figure 5. In-silico model evaluation
Comparison of the expression patterns detected in our study to those observed in Squamous cell Carcinomas (SSC; GSE2503 dataset) and Melanomas (MM; GSE12391 dataset). Fig. 5A: Heatmap MC1R expression pattern showed a positive correlation among datasets (p-value <0.005). Fig. 5B: Heatmap CDKN2A expression pattern showed a positive correlation among datasets (p-value <0.06). Fig. 5C: Subset of genes with an inverse expression pattern between mutant CDKN2A skin cells and SSC and MM. INV: inversely correlated pattern.

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