Chromosomal instability as manifested by increases in aneuploidy and structural chromosome aberrations is believed to play a critical role in the intermediate to late stages in the development of cervical malignancies. The current study was designed to determine the role of tetraploidy in the formation of aneuploidy and ascertain the occurrence of these alterations during the earlier stages of cervical carcinogenesis. Cervical cell samples, with diagnoses ranging from Normal to high-grade lesions, (HSIL) were obtained from 143 women and were evaluated for chromosomal alterations using dual-probe fluorescence in situ hybridization. Cervical cells from a subset of the group were also evaluated for chromosomal instability in the form of micronuclei. The frequencies of cells exhibiting either tetrasomy or aneusomy for Chromosomes 3 and 17 increased significantly with disease progression and displayed distinctive patterns where aneusomy was rarely present in the absence of tetrasomy. The frequencies of micronuclei that formed through either chromosomal loss or breakage increased significantly in both the low-grade and high-grade diagnostic categories and were highly correlated with both the number of tetrasomic and aneusomic cervical cells. In addition, a unique chromosomal alteration involving a significant non-random loss of Chromosome 17 specific to near-tetraploid aneusomic cells (trisomy 17 and tetrasomy 3) was observed. We conclude that tetraploidy and chromosomal instability are related events occurring during the early stages of cervical carcinogenesis that predispose cervical cells to the formation of aneuploidy frequently involving the loss of Chromosome 17.

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Most cancers arise in epithelial tissues and these tissues are typically the targets of the carcinogens responsible for the tumors. Exfoliated epithelial cells have traditionally been used for cancer screening by cytopathologists and these cells also can be used for biomonitoring of genotoxic effects in humans. Cervical cancer results from the progression of preinvasive precursor lesions, called low-grade squamous intraepithelial lesions (LGSILs), to high-grade squamous intraepithelial lesions (HGSILs). The gradient from low to high-grade lesions is characterized by increasing nuclear atypia and the failure of cellular differentiation in progressively more superficial levels of the epithelium. These phenotypic changes are hypothesized to be accompanied by increased genetic instability that can be documented using the micronucleus (MN) assay in exfoliated cervical cells. A retrospective study was performed to investigate the frequency of micronucleated cells in cervical smears from women at high risk for developing cervical cancer. Papanicolaou (Pap) smears from 275 women previously studied at a cancer clinic were coded and analyzed for the frequency of micronucleated cells. LGSIL, HGSIL, and invasive carcinoma smears had significantly higher frequencies than normal and ASCUS (abnormal squamous cells of undetermined origin) smears. HGSIL or severely dysplastic smears had the highest frequency of micronucleated cells (although not significantly higher than LGSIL smears), an observation that that could be useful in confirming these types of lesions. The results indicate that the MN frequency in exfoliated cervical cells may be an additional criterion for establishing cervical cancer risk.

Previous studies in rat, showing a transient pattern of expression of the alpha 7 nicotinic acetylcholine receptor in the ventrobasal thalamus and barrel cortex during the first 2 postnatal weeks, suggest that these receptors may play a role in development of the thalamocortical system. In the present study, in situ hybridization and radiolabeled ligand binding were employed to examine the spatiotemporal distribution of alpha 7 mRNA and alpha-bungarotoxin binding sites in the thalamocortical pathway of mouse during early postnatal development. As in the rat, high levels of alpha 7 mRNA and alpha-bungarotoxin binding sites are present in the barrel cortex of mouse during the first postnatal week. Both alpha 7 mRNA and its receptor protein are observed in all cortical laminae, with the highest levels seen in the compact cortical plate, layer IV, and layer VI. When viewed in a tangential plane, alpha 7 mRNA and alpha-bungarotoxin binding sites delineate a whisker-related barrel pattern in layer IV by P3-5. Quantitative analysis reveals a dramatic decrease in the levels of expression of alpha 7 mRNA and alpha-bungarotoxin binding sites in the cortex by the end of the second postnatal week. Unlike in the rat, only low levels of alpha 7 mRNA or alpha-bungarotoxin binding sites are present in the ventrobasal complex of the mouse thalamus. The broad similarities between the thalamocortical development of rat and mouse taken together with the present results suggest that alpha 7 receptors located on cortical neurons, rather than on thalamic neurons, play a role in mediating aspects of thalamocortical development.

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