Abstract
The incidence of skin cancer is increasing worldwide and cutaneous squamous cell carcinomas (SCCs) are associated with considerable morbidity and mortality, particularly in immunosuppressed individuals (‘carcinomatous catastrophy’). Yet, molecular mechanisms are still insufficiently understood. Besides ultraviolet (UV)-indicative mutations, chromosomal aberrations are prominent. As telomeres are essential in preserving chromosome integrity, and telomere erosion as well as aberrant spatial telomere distribution contribute to genomic instability, we first established telomere length profiles across the whole tissue and identified normal skin (10/30) harboring discrete epidermal sites (stem cell territories) of evenly short telomeres. Precancerous actinic keratoses (AKs) (17) and SCCs (27) expressed two telomere phenotypes: (i) tissue-wide evenly short to intermediate and (ii) longer and tissue-wide heterogeneous telomere lengths, suggesting two modes of initiation, with one likely to originate in the epidermal stem cells. Although tumor histotype, location, patient gender or age failed to distinguish the two SCC telomere phenotypes, as did telomerase activity, we found a trend for a higher degree of aberrant p53 and cyclin D1 expression with long/heterogeneous telomeres. In addition, we established an association for the short/homogeneous telomeres with a simpler and the heterogeneous telomeres with a more complex karyotype correlating also with distinct chromosomal changes. SCCs (13) from renal transplant recipients displayed the same telomere dichotomy, suggesting that both telomere subtypes contribute to ‘carcinomatous catastrophy’ under immunosuppression by selecting for a common set (3, 9p and 17q) and subtype-specific aberrations (e.g., 6p gain, 13q loss). As a second mechanism of telomere-dependent genomic instability, we investigated changes in telomere distribution with its most severe form of telomeric aggregates (TAs). We identified a telomere length-independent but progression-dependent increase in cells with small telomere associations in AKs (17/17) and additional TAs in SCCs (24/32), basal cell carcinomas (30/31) and malignant melanomas (15/15), and provide evidence for a reactive oxygen species-dependent mechanism in this UV-induced telomere organization-dependent genomic instability.
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Acknowledgements
We thank Angelika Lampe for her help in preparing the manuscript, Manuel Berning for constructive discussions and Iris Martin and Katrin Schmidt for their excellent technical assistance. We also thank Catherine Harwood, Charlotte Proby and Irene Leigh from the Cancer Research UK Skin Tumour Laboratory for providing us with the tumor material from the RT recipients. We further thank Dako (Denmark) for generously providing us with telomeric PNA probe. This work was supported by grants from the Deutsche Krebshilfe eV (Tumorstammzellverbund) and Bmbf (UVA Kompetenzverbund) (to PB), Tumorzentrum Heidelberg/Mannheim (to AJ and PB), the Deutsche Forschungsgemeinschaft (SFB873 to PB and SFB 829, Z2 to CM) and supported by contract research ‘Adulte epidermale Stammzellen’ of the Baden-Württemberg Stiftung’ (P-BWS-ASII/35).
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Leufke, C., Leykauf, J., Krunic, D. et al. The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas. Oncogene 33, 3506–3518 (2014). https://doi.org/10.1038/onc.2013.323
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DOI: https://doi.org/10.1038/onc.2013.323