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Conclusions: The results of this study confirm that both smoking of tobacco and alcohol consumption are risk factors for oral and oropharyngeal squamous cell carcinoma (OOSCC). The use of moist snuff had no effect on the risk of OOSCC, probably due to the low levels of tobacco-specific N-nitrosamines in Swedish moist snuff., Objective: The aims of this population-based case-control study in southern Sweden were to establish risk estimates for cigarette and alcohol consumption and to evaluate whether Swedish moist snuff is a risk factor for OOSCC., Material and Methods: Between September 2000 and January 2004, 132/165 consecutive cases (80%) diagnosed with OOSCC and 320/396 matched controls (81%) were investigated. All subjects were interviewed and examined according to a standardized protocol., Results: Individuals who drank > or =350 g of alcohol/week showed an increased risk of OOSCC (OR 2.6; 95% CI 1.3-5.4). Total lifetime consumption of tobacco for smoking (>250 kg) had a dose-response effect on the risk of OOSCC (OR 4.7; 95% CI 2.4-9.1). We found no increased risk of OOSCC associated with the use of Swedish moist snuff (OR 1.1; 95% CI 0.5-2.5).

A human tumor xenograft (L56Br-X1) was established from a breast cancer axillary lymph node metastasis of a 53-year-old woman with a BRCA1 germ-line nonsense mutation (1806C>T; Q563X), and a cell line (L56Br-C1) was subsequently derived from the xenograft. The xenograft carries only the mutant BRCA1 allele and expresses mutant BRCA1 mRNA but no BRCA1 protein as determined by immunoprecipitation or Western blotting. The primary tumor, lymph node metastasis, and xenograft were hypodiploid by DNA flow cytometry, whereas the cell line displayed an aneuploidy apparently developed via polyploidization. Cytogenetic analysis, spectral karyotyping, and comparative genomic hybridization of the cell line revealed a highly complex karyotype with numerous unbalanced translocations. The xenograft and cell line had retained a somatic TP53 missense mutation (S215I) originating from the primary tumors, as well as a lack of immunohistochemically detectable expression of steroid hormone receptors, epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER-2), and keratin 8. Global gene expression analysis by cDNA microarrays supported a correlation between the expression profiles of the primary tumor, lymph node metastasis, xenograft, and cell line. We conclude that L56Br-X1 and L56Br-C1 are useful model systems for studies of the pathogenesis and new therapeutic modalities of BRCA1-induced human breast cancer.

Head and neck squamous cell carcinomas (HNSCC) are often characterized by complex karyotypic changes, and a substantial proportion of the reported tumors have shown intratumor heterogeneity in the form of cytogenetically related (40%) or unrelated clones (20%). In order to study intratumor heterogeneity and to distinguish the temporal order of chromosome rearrangements in these tumors, two or more samples from different areas of the same tumor were separately examined in 19 HNSCC, yielding karyotypes from a total of 42 tumor samples. Intrasample heterogeneity was observed in 16 samples. Two samples displayed both related and unrelated multiple clones, four samples showed only multiple unrelated clones, and the remaining 10 samples had only related subclones. Intersample heterogeneity was detected in all but one tumor. Five tumors showed both cytogenetically related and unrelated multiple clones, 11 were found to have only related subclones, and the remaining two tumors showed only unrelated clones. Clonal evolution could be assessed in 13 tumors. A comparison of chromosome imbalances in different subclones from these tumors suggests that partial or entire loss of 3p, 8p, 9p, and 18q and gain of genetic material from 3q and 8q are likely to be early genetic events. In contrast, loss of 1q, 6p, 7q, and chromosome 10, as well as gain of chromosome arms 5p and 7p, are most probably later genetic events. One of the examined tumors contained two highly complex clones that were cytogenetically unrelated, indicating that this tumor had a multicellular origin.

CCND1 amplification results in cyclin D1 overexpression. However, other unidentified genetic mechanisms contribute to enhanced gene expression. In the present study, 32 squamous cell carcinoma of the head and neck (SCCHN) were investigated regarding chromosomal abnormalities involving 11q13 by cytogenetic analysis, genomic CCND1 amplification by differential PCR and FISH, and cyclin D1 expression on the mRNA and protein level by differential RT-PCR and immunohistochemistry, respectively. CCND1 amplification, observed in 11 of 32 (34%) tumours, resulted in overexpression of cyclin D1 on the mRNA and/or protein level, in 3 cases in association with chromosomal translocations. In cytogenetic analysis, 4 tumours had hsr(11)(q13), all of which showed CCND1 amplification and cyclin D1 overexpression. Overexpression of cyclin D1 was detected at the mRNA level in 23 tumours (72%) and on the protein level in 25 tumours (78%). In one case a translocation was seen together with cyclin D1 overexpression on the mRNA level, without any cytogenetic or molecular signs of amplification. Furthermore, cases with cyclin D1 overexpression were frequently observed in the absence of any genomic rearrangement. We conclude that, besides amplifications, chromosomal translocations and other transcriptional or translational regulatory mechanisms are involved in CCND1 deregulation.