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Deregulated Expression of c-mos in Non-Small Cell Lung Carcinomas: Relationship with p53 Status, Genomic Instability, and Tumor Kinetics

Departments of Histology and Embryology, School of Medicine [V. G. G., P. Z., G. M., S. K., N. K., A. K., A. A., P. F., J. I., C. K.], and Cardiac Surgery [P. J. A.], University of Athens, Athens, Greece; Roy Castle International Centre for Lung Cancer Research, Liverpool, United Kingdom [V. G. G., P. Z., T. L., J. K. F.]; Bristol Heart Institute, University of Bristol, Bristol, United Kingdom [A. A.]; Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece [V. Z.]; Laboratory of Cell Proliferation and Ageing, Institute of Biology, NCSR "Demokritus," Athens, Greece [D. K.]; and Baylor College of Medicine, Houston, Texas 77030 [P. J. A.]

Little is known about the status of the mitogen-activating protein kinase pathways in lung cancer. One of the key molecules taking part in these pathways is the product of the c-mos proto-oncogene, which plays an important role in oocyte maturation. In vitro investigations in somatic cells have shown that c-mos expression has opposing effects on the cell cycle, which suggests that this proto-oncogene may represent an important determinant of aberrant cell function (genomic instability and altered kinetics). A recent study suggests that these effects may be p53 dependent. In view of the apparent link between c-mos and p53, we investigated in a series of 56 non-small cell lung carcinomas: a) the status of c-mos; b) its relationship to genomic instability (aneuploidy) and two kinetic parameters of the tumors, proliferation and apoptotic indexes (AI); and c) its association with p53 alterations and their concomitant relationship with the above parameters.

We found c-mos overexpression in 27% of the tumors. Expression was higher in stages II/III (34%) than in stage I (17%; P = 0.018). Complete concordance was observed between c-mos overexpression and elevated c-mos mRNA levels. Because c-mos gene amplification was not detected, its deregulated expression may be attributable to increased transcription. Of the c-mos positive [c-mos(P)] cases, 77% were associated with aneuploidy. Sequencing showed two silent mutations and one missense (RL) at codon 22, located in a region critical for c-mos stability. In contrast to the findings of some in vitro studies, c-mos(P) tumors had a lower mean AI score than the c-mos negative [c-mos(N)] tumors had, implying that induction of apoptosis may have been defective. Indeed, 86% of the tumors overexpressing c-mos showed p53 alterations. The carcinomas with concomitant alterations of c-mos and p53 [c-mos(P)/p53 positive] had significantly lower AI values (P < 0.001) and were more frequently associated with aneuploidy (P = 0.015) than the c-mos(N)/p53 negative tumors but not the c-mos(N)/p53 positive tumors, which suggests that p53 status is the main determinant of ploidy status and apoptosis in our series. This finding also strengthens the concept that wild-type p53 plays a "safeguard" role in preventing oncogene-mediated activation.

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