Deregulated expression of c-mos in non-small cell lung carcinomas: Relationship with p53 status, genomic instability, and tumor kinetics

Little is known about the status of the mitogen-activating protein kinase p athways in lung cancer. One of the key molecules taking part in these pathw ays is the product of the c-mos proto-oncogene, which plays an important ro le in oocyte maturation. In vitro investigations in somatic cells have show n that c-mos expression has opposing effects on the cell cycle, which sugge sts that this proto-oncogene may represent an important determinant of aber rant cell function (genomic instability and altered kinetics). A recent stu dy suggests that these effects may be p53 dependent. In view of the apparen t link between c-mos and p53, we investigated in a series of 56 non-small c ell lung carcinomas: a) the status of c-mos; b) its relationship to genomic instability (aneuploidy) and two kinetic parameters of the tumors, prolife ration and apoptotic indexes (AI); and c) its association with p53 alterati ons and their concomitant relationship with the above parameters. We found c-mos overexpression in 27% of the tumors. Expression was higher i n 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 expressi on may be attributable to increased transcription. Of the c-mos positive [c -mos(P)I cases, 77% were associated with aneuploidy. Sequencing showed two silent mutations and one missense (R-->L) at codon 22, located in a region critical for c-mos stability. In contrast to the findings of some irt vitro studies, c-mos(P) tumors had a lower mean AI score than the c-mos negative [c-mos(IV)] tumors had, implying that induction of apoptosis may have been defective. Indeed, 86% of the tumors overexpressing c-mos showed p53 alter ations. The carcinomas with concomitant alterations of c-mos and p53 rc-mos (P)/p53 positive] had significantly lower AI values (P < 0.001) and were mo re 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 th at 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.