Universität zu Köln

Leufke, C., Leykauf, J., Krunic, D., Jauch, A., Holtgreve-Grez, H., Boehm-Steuer, B., Broecker, E-B, Mauch, C., Utikal, J., Hartschuh, W., Purdie, K. J. and Boukamp, P. (2014). The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas. Oncogene, 33 (27). S. 3506 - 3519. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Leufke, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Leykauf, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krunic, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jauch, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Holtgreve-Grez, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boehm-Steuer, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Broecker, E-B UNSPECIFIED UNSPECIFIED UNSPECIFIED Mauch, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Utikal, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartschuh, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Purdie, K. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boukamp, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-434108
DOI:	10.1038/onc.2013.323
Journal or Publication Title:	Oncogene
Volume:	33
Number:	27
Page Range:	S. 3506 - 3519
Date:	2014
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NONMELANOMA SKIN-CANCER; IN-SITU HYBRIDIZATION; GENOMIC INSTABILITY; ACTINIC KERATOSIS; P53 MUTATIONS; GENE; BASAL; HTERT; TRANSPLANTATION; LOCALIZATION Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43410