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Chromosomal aberrations were analyzed in 12 established cell lines derived from laryngeal squamous cell carcinoma. Cytogenetic and fluorescence in situ hybridization studies were used to identify aberrations in the 11q13 region and in some other chromosome regions. Amplification of 11q13 was established only in the cell lines derived from subjects with a survival period of less than 5 years and, together with the 3q gain, were the only chromosomal structural abnormalities connected with short survival. In this group we also found translocations with a breakpoint within 11q13. In three cell lines, 11q13 was observed as a homogenously staining region. The results suggest that amplification of 11q13, as well as re-arrangements potentially involved in up-regulation of the oncogenes mapped in 11q13, should be considered as markers of poor prognosis in laryngeal cancer. A diagnostic significance of 11q13 may be increased by a parallel determination with 3q gain.

Comparative genomic hybridization was performed on 38 primary laryngeal carcinomas divided into two groups according to the metastatic phenotype. DNA copy number changes were detected in 22 of the 38 cases (57.9%). Gains were most frequently observed at 3q, 8q, and 9q, and losses were found in decreasing order at 18q, 3p, and 4. The mean value of losses was 2.5 times as high in metastasizing primary tumors (23/38) as in nonmetastasizing tumors. The most frequent losses in metastasizing tumors were at 18q, 3p, and 5q.

Megakaryocytic blast crisis occurs extremely rarely, accounting for3% of cases of chronic myelogenous leukemia in blastic transformation. In chronic myeloid leukemia, a variant Philadelphia translocation is reported in 2-10% of cases. We report an unusual case of megakaryocytic blast crisis with the Philadelphia variant rearrangement t(9;22;22) and a constitutional translocation t(3;7). The breakpoint in the 22q13 region was involved in this translocation. The chromosome region 22q13 harbors MKL1 gene, which is engaged in a specific translocation associated with acute megakaryoblastic leukemia. Study of deregulation of these four genes could contribute to better understanding of the effects of the t(9;22;22) rearrangement in a megakaryocytic blast crisis.

The majority of classical tumor suppressor genes, such as CDKN2A or RB1, were identified by delineation of biallelic losses called homozygous deletions. To systematically identify homozygous deletions in laryngeal squamous cell carcinoma and to unravel novel putative tumor suppressor genes we screened three laryngeal squamous cell carcinoma cell lines (LSCC) using array comparative genomic hybridization (array-CGH). Out of 31 candidate regions for homozygous deletions identified by array-CGH, 5 were verified further by PCR. Among others, these homozygous deletions affected the tumor suppressor gene CDKN2A and the apoptosis-inducing STK17A gene. To assess the frequency of the identified deletions we investigated the affected sites in 9 additional LSCC cell lines. In 5 of the 9 cell lines the CDKN2A gene was homozygously lost. Thus, CDKN2A was homozygously deleted in 7 of the 12 cell lines. No other recurrent homozygous deletions were found. Homozygous deletions was a frequent mechanism of CDKN2A inactivation. Moreover, we identified several other genes, including the putative tumor suppressor gene STK17A, which may be inactivated by homozygous deletions and thus are potentially implicated in laryngeal squamous cell carcinoma development.

Our recent comparative genomic hybridization (CGH) study has shown that losses of the long arm of chromosome 13 were the most common aberrations in primary larynx tumors and their corresponding metastases. In the present study, 20 pairs of primary larynx tumors and their metastases were analyzed by interphase fluorescence in situ hybridization (FISH) with three different 13q-specific probes (RB1, D13S25, and 13qtel). Our experiments were generally consistent with the CGH results, with some differences indicating cell population heterogeneity in the analyzed cohort of tumors. The results provided further evidence for the putative role of the RB1 gene alterations in the metastatic process, although a contribution by other gene(s) during metastasis cannot be ruled out.

1. Institute of Human Genetic, Polish Academy of Sciences, Poznan, Poland 2. Department of Otolaryngology, Poznan University of Medical Sciences, Poland 3. Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Germany 4. Department of OtorhinolaryngologyeHead and Neck Surgery and Department of Medical Biochemistry, Turku University Central Hospital and Turku University, Finland