Research Project Tumorzentrum Heidelberg/Mannheim
Prof. Dr. sc. hum. Anna Jauch
Institut für Humangenetik
INF 366, 69120 Heidelberg, Phone: +49 (0)6221 56-5407
Prof. Dr. rer. nat. Petra Boukamp
DKFZ, Abteilung Genetik des Hautcarcinogenes
INF 280, 69120 Heidelberg, Phone: +49 (0)6221 424-516
Identification of a new skin carcinoma-relevant genetic aberration and its potential mode of induction
Background: Basal cell (BCC) and squamous cell carcinomas (SCC) of the skin are the most frequent tumors worldwide with increasing incidence. Except for UV-B radiation (mutations in the p53 tumorsuppressor gene and ras oncogene) and a potential contribution of the human papilloma virus (HPV), little is known about the development of the complex karyotype characteristically seen in SCCs. We now have evidence that gain of chromosome 11q is a frequent aberration. The same aberration can be induced in our experimental HaCaT skin carcinogenesis model by increased temperature resulting in tumorigenic conversion of the cells. Furthermore, we have demonstrated that the ends of the chromosomes, the telomeres, are involved in chromosome aberrations. Under certain conditions, the rather evenly distributed telomeres form clusters, telomeric aggregates (TA) and these TAs are causally related to translocation chromosomes.
Goals: We want to characterize the role of TAs as a causal mechanism for 11q gain in skin carcinomas and to elucidate whether TAs are suitable diagnostic markers for genomic instability also in clinical settings.
Methods: Using comparative genomic hybridization (CGH) we intend to define the relevant 11q region in SCCs. On the other hand, we determine whether TAs are present in SCCs with aberrant chromosomes 11 and whether this chromosome is more frequently involved in experimentally induced TAs than other chromosomes.
Scientists of Institut für Humangenetik
Dr. rer. nat. Barbara Böhm-Steuer
Dr. med. Martin Granzow
Dr. rer. nat. Susanne Popp
Scientists of DKFZ
Department Genetik der Hautcarcinogenese
Bettina Burnworth (PhD Student)
- Leufke C, Leykauf J, Krunic D, Jauch A, Holtgreve-Grez H, Böhm-Steuer B, Bröcker EB, Mauch C, Utikal J, Hartschuh W, Purdie KJ, Boukamp P (2013). The telomere profile distinguishes two classes of genetically distinct cutaneous squamous cell carcinomas. Oncogene 33(27):3506-18.
- Boukamp P, Mirancea N. (2007). Telomeres rather than telomerase a key target for anti-cancer therapy? Exp Dermatol 16:71-9.
- Crabbe L, Jauch A, Naeger CM, Holtgreve-Grez H, Karlseder J. (2007):Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc Natl Acad Sci USA, 104:2205-2210.
- Burnworth B, Popp S, Stark HJ, Steinkraus V, Brocker EB, Hartschuh W, Birek C, Boukamp P. (2006): Gain of 11q/cyclin D1 overexpression is an essential early step in skin cancer development and causes abnormal tissue organization and differentiation. Oncogene 25:4399-412.
- Burnworth B, Arendt S, Muffler S, Steinkraus V, Brocker EB, Birek C, Hartschuh W, Jauch A, Boukamp P. (2006). The multi-step process of human skin carcinogenesis: A role for p53, cyclin D1, hTERT, p16, and TSP-1.Eur J Cell Biol. Dec 30
- Boukamp P, Popp S, Krunic D. (2005): Telomere-dependent chromosomal instability. J Investig Dermatol Symp Proc 10:89-94.
- Louis SF, Vermolen BJ, Garini Y, Young IT, Guffei A, Lichtensztejn Z, Kuttler F, Chuang TC, Moshir S, Mougey V, Chuang AY, Kerr PD, Fest T, Boukamp P, Mai S. (2005): c-Myc induces chromosomal rearrangements through telomere and chromosome remodeling in the interphase nucleus. Proc Natl Acad Sci U S A 102:9613-8.
- Ermler S, Krunic D, Knoch TA, Moshir S, Mai S, Greulich-Bode KM, Boukamp P. (2004): Cell cycle-dependent 3D distribution of telomeres and telomere repeat-binding factor 2 (TRF2) in HaCaT and HaCaT-myc cells. Eur J Biol 83:681-690.
- Chuang TC, Moshir S, Garini Y, Chuang AY, Young IT, Vermolen B, van den Doel R, Mougey V, Perrin M, Braun M, Kerr PD, Fest T, Boukamp P, Mai S. (2004): The three-dimensional organization of telomeres in the nucleus of mammalian cells. BMC Biol 2:12.
- Popp S, Waltering S, Herbst C, Moll I, Boukamp P. (2002): UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas. Int J Cancer 99:352-60.
- Popp S, Waltering S, Holtgreve-Grez H, Jauch A, Proby C, Leigh IM, Boukamp P. (2000): Genetic characterization of a human skin carcinoma progression model: from primary tumor to metastasis. J Invest Dermatol 115:1095-103.