FREQUENT LOSS OF HETEROZYGOSITY ON CHROMOSOME-4 IN DIETHYLNITROSAMINE-LNDUCED C3H MSM MOUSE HEPATOCELLULAR CARCINOMAS IN CULTURE/

Genetic changes, in particular the loss of heterozygosity (LOH) and th e presence of c-Ha-ras codon 61 point mutations, were investigated in diethylnitrosamine-induced hepatocellular carcinomas (HCCs) in C3H/MSM F-1 mice. (MSM are wild mice.) LOH analysis of 48 primary tumors with microsatellite probes covering at least one proximal and one distal s ite of each autosome revealed no obvious positive results for LOH. Ana lysis of 23 cell lines established from seven of these HCCs, however, showed LOH on chromosome 4 in all (seven of seven), even in early pass ag2s (GZ-G3). With regard to other chromosomes, LOH was observed only rarely on chromosomes 16 and 19. These allelotype features were mainta ined in later passages (G11-G14), with only a few additional occurrenc es of LOH appearing on chromosomes 1, 6, and 8. Extensive analyses wit h multiple microsatellite probes from chromosome 4 and with 52 cell li nes established from 24 HCCs of 18 mice revealed LOH in 22 of the tumo rs (92%), with the shortest region about 10 cM distal to the alpha-int erferon gene. No c-Ha-ras oncogene activation in codon 61 was observed . These data indicate that loss of tumor suppressor genes on chromosom e 4 may play an important role in mouse hepatocarcinogenesis in progre ssion in vivo or in immortalization in vitro or both, (C) 1995 Wiley-L iss, Inc.