Genomic alterations associated with loss of heterozygosity for TP53 in Li -Fraumeni syndrome fibroblasts

Studies of Li-Fraumeni syndrome fibroblasts heterozygous for germline TP53 mutations have shown that loss of heterozygosity (LOH) occurs during passag ing and is associated with genomic instability, such as chromosomal aberrat ions and aneuploidy. to investigate the genomic changes associated with LOH in Li-Fraumeni (LF) fibroblasts, we have analysed cell strains at increasi ng population doublings (PD) using Comparative Genomic Hybridization (CGH). We have looked at three groups of cell strains: LF mutation-carrying strai ns which showed LOH for TP53, LF mutation-carrying strains which did not sh ow LOH, and strains from normal individuals. Using CGH, we have detected lo ss of distinct chromosomal regions associated with LOH in 4 out of 5 mutati on-carrying strains. In particular we have found loss of chromosomal region s containing genes involved in cell cycle control or senescence, including loss of 9p and 17p in these strains. Other recurrent changes included loss of chromosomes 4q and 6q, regions shown to contain one or more tumour suppr essor genes. No genomic alterations were detected at cumulative PD in the n ormal strains or in the LF mutation-carrying strains which did not show LOH for TP53. We have also analysed the three groups of strains for microsatel lite instability and somatic TP53 mutations, and have found genetic alterat ions in only one strain. (C) 2000 Cancer Research Campaign.