0165-4608/99/$–see front matter PII S0165-4608(98)00136-8 Cancer Genet Cytogenet 108:154–157 (1999)  Elsevier Science Inc., 1998 655 Avenue of the Americas, New York, NY 10010 Bleomycin-Induced Chromosome Aberrations in Lymphocytes Derived from Patients with Lamellar Ichthyosis Patrizia Vernole, Angela Tullio, Daniela Caporossi, Biagio Didona, Gerry Melino, and Bruna Tedeschi ABSTRACT: Patients affected by some genetic skin defects, for example, dyskeratosis congenita or scle- roderma, may present spontaneous or induced chromosomal fragility. Hence we performed a cytoge- netic analysis in families of patients affected by lamellar ichthyosis, an autosomal recessive disease not yet fully characterized at the cellular and molecular levels. Chromosomal fragility was assayed in untreated lymphocyte cultures and in those supplemented with aphidicolin or bleomycin. Cells from some affected patients and some of their parents showed hypersensitivity to the radiomimetic agent bleomycin. © Elsevier Science Inc., 1998 INTRODUCTION Lamellar ichthyosis (LI) is a rare autosomal recessive dis- ease (with an incidence of about 1 in 250,000 in Caucasian populations) that is characterized by abnormalities of the stratum corneum, the most exterior layer of the epidermis [1]. Clinically, the disease shows a high degree of hetero- geneity. In the most severe cases, a translucent collodion membrane is present at birth. In some adults, the disease appears as large brown plate-like scales covering the entire body, whereas in others, the scales are smaller and sporadic. Genetic heterogeneity is evident in LI. Point mutations of the transglutaminase 1 gene (TGM1), localized in 14q11, have been observed in some patients [2, 3]. We have re- cently shown that these mutations result in the loss of ac- tivity or of the proteolytic activation of TGM1 [4], result- ing in abnormalities of the formation of the cornified envelope [5]. In other families, there is a linkage between the disease and the 2q33–35 region [6]. In other cases, no linkage was found with either 14q or 2q. Recently, some cases of squamous cell carcinoma have been reported in LI patients, despite the rare occurrence of the disease itself [7]. Patients affected by other inherited skin diseases, for example, xeroderma pigmentosum, basal cell nevus syndrome, or dyskeratosis congenita, are at a higher risk of developing tumors, often localized in the skin. In parallel, these patients show an in vitro chromo- somal fragility, which may be spontaneous or induced by various agents [8–10]. Because the skin is a complicated model of cell death, where both apoptosis and death by keratinization occur [5, 11], and in both cases transgluta- minases are involved [5], abnormalities in cell death path- ways might indeed influence the development of cancer. Therefore we investigated the cytogenetics of lymphocytes in LI families. We analyzed karyotypes, chromosomal aberrations, and sister chromatid exchanges (SCE) expressed spontane- ously in culture. Moreover, we assayed the clastogenic ef- fects of two drugs commonly used for cytogenetic tests in vitro: aphidicolin (APC) and bleomycin (BLM). Aphidi- colin is an inhibitor of DNA polymerases  and , mainly involved in DNA synthesis but also in DNA repair [12]. Aphidicolin is able to induce nonrandom chromosome gaps and breaks, at the so-called “fragile sites” [13]. Bleo- mycin is an antitumoral glycopeptide, which is defined as a radiomimetic agent due to its ability to cause DNA sin- gle- and double-strand breaks and chromosome damage in all phases of the cell cycle, similarly to ionizing radiation (for review see [14]). Bleomycin was used in vitro to test chromosomal fragility of healthy subjects and of patients affected by various kinds of diseases, such as inherited or sporadic tumors [15, 16] and other dermatological dis- eases, such as dyskeratosis congenita [8] and scleroderma [17]. It has been postulated that a higher degree of damage is associated with less efficient DNA repair, and hence with a higher risk of developing tumors, such as in rela- tives of tumor-affected subjects [15]. From the Department of Public Health and Cell Biology, Uni- versity “Tor Vergata” (P. V., A. T., D. C., B. T.) and the Biochemis- try Laboratory, Instituto Dermopatico dell’Immacolata, IDI-IRCCS (B. D., G. M.) Rome, Italy. Address reprint requests to: Dr. P Vernole, Dip Sanità Pub- blica e Biologia Cellulare, Università di Roma “Tor Vergata,” via Tor Vergata 135, 00133 Rome, Italy. Received June 13, 1997; accepted May 26, 1998.