UV-B-type mutations and chromosomal imbalances indicate common pathways for the development of Merkel and skin squamous cell carcinomas

Authors

  • Susanne Popp,

    1. Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
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    • The first two authors contributed equally to this work.

  • Stefan Waltering,

    1. Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
    2. Department of Dermatology, Mannheim Medical School, University of Heidelberg, Mannheim, Germany
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    • The first two authors contributed equally to this work.

  • Christel Herbst,

    1. Department of Dermatology, Mannheim Medical School, University of Heidelberg, Mannheim, Germany
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  • Ingrid Moll,

    1. Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany
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  • Petra Boukamp

    Corresponding author
    1. Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Heidelberg, Germany
    • Division of Genetics of Skin Carcinogenesis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany
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    • Fax: +49-6221-424551


Abstract

Two developmentally highly divergent nonmelanoma skin cancers, the epidermal squamous cell carcinomas (SCC) and the neuroendocrine Merkel cell carcinomas (MCC), occur late in life at sun-exposed body sites. To determine whether these similarities may indicate common genetic alterations, we studied the genetic profile of 10 MCCs and analyzed 6 derived cell lines and 5 skin SCC lines by comparative genomic hybridization (CGH) and molecular genetic analyses. Although the MCCs were highly divergent—only 3 of the 10 tumors exhibited common gains and losses—they shared gain of 8q21-q22 and loss of 4p15-pter with the genetically much more homogeneous SCC lines. In addition, 2 of 5 SCC and 2 of 6 MCC lines exhibited UV-B-type-specific mutations in the p53 tumor-suppressor gene and a high frequency (9/11) of CC→TT double base changes in codon 27 of the Harvey (Ha)-ras gene. Since 45% of the tumor lines were homozygous for this nucleotide substitution compared to 14% of the controls and in 1 MCC patient the wild-type allele was lost in the tumor, this novel polymorphism may contribute to tumor development. On the other hand, loss of 3p, characteristic for SCCs, was rare in MCCs. Although in 2 of 3 SCC lines 3p loss was correlated with reduced expression of the FHIT (fragile histidine triad) gene, the potential tumor suppressor mapped to 3p14.2 and 2 MCC lines with normal 3p showed aberrant or no FHIT transcripts. Taken together, in addition to the common UV-B-specific mutations in the p53 and Ha-ras gene, MCCs and SCCs also share chromosomal imbalances that may point to a common environmental-derived (e.g., UV-A) oxidative damage. © 2002 Wiley-Liss, Inc.

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