A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li – Fraumeni patients carrying a mutation to the TP53 gene

Abstract

We have studied a total of 36 tumours from 28 patients with germline mutations to the TP53 gene for loss of heterozygosity at TP53 using techniques of both direct sequencing and restriction fragment length polymorphism analysis. All patients were from families conforming to the de®nition of classical Li ± Fraumeni syndrome (LFS) or were Li ± Fraumeni-like (LFL). The data we have obtained show that loss of the wild-type TP53 gene is observed in under half (44%) of all tumours, and that the pattern of LOH at TP53 may be mutation speci®c. LOH has been observed in premalignant as well as invasive tumours. Two tumours (6%) show loss of the mutant allele and retention of the wild-type. To con®rm that TP53 is indeed the target for LOH events on chromosome 17, we have used additional microsatellite repeats to examine patterns of allelic imbalance along the length of chromosome 17. Data from this analysis indicate that TP53 is the target of loss, but reveal some other interesting patterns of allelic imbalance at other loci on chromosome 17.

Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild-type p53 allele in only 50% of tumours

“…Two out of four tumours analysed in family A and one of two in family B showed loss of the wild-type p53 allele at the site of the germline mutation, while the remaining tumours retained heterozygosity. This pattern is in agreement with published data, in which the fraction of tumours with loss of heterozygosity ranges from 44% to 69% (Varley et al, 1997). Our results are further supported by immunohistochemistry with the anti-p53 antibody, which indicated the accumulation of the p53 protein in tumours that have lost the wild-type allele.…”

“…There are several single-case reports and one recent larger study indicating, however, that loss of heterozygosity is not observed in a significant fraction of these tumours (Varley et al, 1997).…”

Mutations of the p53 gene in canine lymphoma and evidence for germ line p53 mutations in the dog

“…Only the remaining wild type allele was detectable ( Figure 6; patient 1). An equivalent situation has also been reported for Li-Fraumeni patients, where loss of the mutant germ line allele and retention of the wild type p53 allele was evident in liposarcoma and in adrenocortical carcinoma (Varley et al, 1997).…”

TP53 DNA contact mutations are selectively associated with allelic loss and have a strong clinical impact in head and neck cancer

“…It is therefore conceivable that the selection pressure exerted by di erent mutation types to eliminate the wild-type allele(s) is also cell type dependent. Indeed, Varley and colleagues (Varley et al, 1997) have reported evidence of a cell type speci®c association between the p53 mutation type in di erent tumour entities from Li ± Fraumeini patients. Whereas in breast tumours DNA contact mutations in codon 248 were accompanied by LOH, in tumours derived from non-epithelial cell types with the same mutations no LOH was observed.…”

“…Indeed, no association was found in HNSCC between loss of heterozygosity (LOH) for the TP53 locus and mutation (Ahomadegbe et al, 1995). Interestingly, in a study on Li-Fraumeini tumour patients, LOH for the wild-type allele was observed in less than half of cases carrying p53 germ line mutations, and there was some evidence for LOH being associated with mutation types (Varley et al, 1997).…”