Puig-Butille Joan Anton, Escámez María José, Garcia-Garcia Francisco, Tell-Marti Gemma, Fabra Àngels, Martínez-Santamaría Lucía, Badenas Celia, Aguilera Paula, Pevida Marta, Dopazo Joaquín, del Río Marcela, Puig Susana
Melanoma Unit, Hospital Clinic and IDIBAPS (Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer), Barcelona, Spain.
Oncotarget. 2014 Mar 30;5(6):1439-51. doi: 10.18632/oncotarget.1444.
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.
CDKN2A基因的种系突变和/或MC1R基因中的红发颜色变体与患皮肤黑色素瘤或非黑色素瘤皮肤癌的易感性增加相关。我们研究了CDKN2A种系突变p.G101W和MC1R变体对与皮肤癌相关的基因表达和转录谱的影响。为此，我们从黑色素瘤易感家族的兄弟姐妹中建立了原代皮肤细胞共培养物，随后使用表达阵列方法进行分析。结果，我们发现1535个转录本在CDKN2A突变细胞中失调，免疫相关基因（HLA-DPB1、CLEC2B、IFI44、IFI44L、IFI27、IFIT1、IFIT2、SP110和IFNK）过表达，而在Notch信号通路中起作用的基因下调。3570个转录本在MC1R变体携带者中失调。特别是，与氧化应激和DNA损伤途径相关的基因以及与帕金森氏症、阿尔茨海默氏症和亨廷顿氏症等神经退行性疾病相关的基因上调。最后，我们观察到在携带CDKN2A突变或MC1R变体的表型正常细胞中鉴定出的表达特征在皮肤癌肿瘤（黑色素瘤和鳞状细胞癌）中得以维持。这些结果表明转录组失调是皮肤癌发展的关键早期事件。
