The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas

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.

Squamous Cell Carcinoma Following Photodynamic Therapy for Cutaneous Bowen’s Disease in a Series of 105 Patients

“…A PDT-stressed cell that expresses telomerase could lead to SCC development. Indeed, it has been shown that telomeres play an important role in skin carcinogenesis (23).…”

Wnt‐3a‐activated human fibroblasts promote human keratinocyte proliferation and matrix destruction

“…SCC development is a multistep process leading to highly complex karyotypes with large cytogenetic heterogeneity . Besides mutational inactivation of Cellular tumor antigen p53, additional aberrations, such as amplification of chromosome 11q13/cyclin D1 or loss of chromosome 15/thrombospondin 1, are known to modulate the cell or its environment .…”

Convergent adaptation of cellular machineries in the evolution of large body masses and long life spans

“…Intraspecies investigations have shown the intricacy of telomere biology: for example telomere length is uneven within individuals and tissues (Leufke et al 2014); telomerase activity is tissue context sensitive (Krunic et al 2009) and replication is not the only mechanism of telomere attrition (von Zglinicki 2002). Notwithstanding this complexity, comparative investigations in cell culture systems have shown fundamental differences among mammals (Seluanov et al 2007; Lorenzini et al 2009; Gomes et al 2011).…”