ROLE OF CHROMOSOME-5 IN IMMORTALIZATION AND TUMORIGENESIS OF HUMAN KERATINOCYTES

Rhim et al. were first to show that superinfection of Ad12-SV40-infect ed immortalized human epidermal cell with an RNA tumor virus containin g a ras oncogene, such as Ki-MSV, or their treatment with chemical car cinogens, leads to the ability of cells to both grow in anchorage-inde pendent fashion and to form tumors in athymic nude mice. We describe d etails of the chromosome changes observed during the transformation. T he culture was monitored through 40 passages after Ad12-SV40 infection . Chromosomes 9 and 11 showed random monosomy during the initial stage s, but by passage 10 clonal evolution of the cell line was well establ ished. Observed chromosome monosomy/trisomy coupled with chromosome re arrangements (identified as chromosomes A through F) were monosomy 13, loss of p arms of 8 and 10, partial loss of 5 (del(5)(q13) and of the q arm of 18(del(18)(q12)), and extra copies of 11q, 20 and 21. During its progression to tumorigenicity, a derived chromosome E containing a segment of 5q, also appeared to play a major role. The cells remaine d immortalized as long as the 5q segment was present in some of the ce ll population as derived chromosomes E or F Derivative chromosome E sh owed noteworthy changes during the progression to tumorigenicity, in b oth viral and chemical transformations. There was loss of heterozygosi ty of 5q due to an exchange of 5q with chromosomes E or F. In Ki-MSV- and 4NQO-transformed cells, presence of an altered chromosome E (ident ified as E1) was observed. In MNNG-treated cells, there was a selectio n of population of cells with further alteration in chromosome E (iden tified as E3). Besides alterations in chromosome E, additional chromos ome changes leading to gene activation and amplification indicating a multistep progression to tumorigenicity were observed. The cytogenetic data reiterate the ever-increasing need for molecular analysis of non random karyotype changes.