Capturing the biological impact of CDKN2A and MC1R genes as an early predisposing event in melanoma and non melanoma skin cancer

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.

Integrated expression profiles analysis reveals novel predictive biomarker in pancreatic ductal adenocarcinoma

“…IFI44L is reported upregulated in human nasopharyngeal carcinoma cells modulated through the downregulation of miR-9 [ 37 ]. In melanoma and non-melanoma skin cancer cells with CDKN2A mutated, IFI44L is also reported upregulated [ 38 ]. However these finding remains at the level of cell biology and none evident was reported that the deregulation of IFI44L may influence the progression or prognosis of cancer.…”

Red hair, MC1R variants, and risk for Parkinson's disease – a meta‐analysis

“…Other studies have also implicated a potential role of general pigmentation in PD. For example, primary skin cultures from individuals with red hair color showed deregulation of genes involved in neurodegenerative diseases such as PD . A clinical study reported a correlation between light pigmentation phenotype and increased echogenicity of the substantia nigra .…”

PRMT1 regulates tumor growth and metastasis of human melanoma via targeting ALCAM

“…The transition from the radial growth phase to the vertical growth phase is responsible for the majority of cancer-associated mortalities caused by melanoma (2). Sun exposure and acquired genetic alterations are two well-established etiologies for melanoma, and previous studies have revealed that congenital germline mutation of certain critical genes, such as cyclin-dependent kinase inhibitor 2A, is another risk factor (3)(4)(5). The diagnostic technology and health consciousness regarding melanoma have greatly improved in recent years and, furthermore, the surgical techniques and adjuvant treatment measures have progressed (6,7).…”