An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53.

Abstract

We present an extended family with LiFraumeni syndrome characterised by gastric and breast carcinoma, glioma, sarcoma, and leukaemia. This family showed strong evidence of linkage to TP53, and three of four tumours analysed showed loss of the wild type allele. A codon 175 missense mutation was identified in exon S in all available affected subjects. Counselling, screening, and issues surrounding presymptomatic testing are discussed. (J Med Genet 1995;32:942-945)

Novel p53 splice site mutations in three families with Li-Fraumeni syndrome

“…Although the splice donor site mutation in intron 1 of family 2 is in the 5' untranslated region, splicing at potential cryptic sites within intron 1 could produce an upstream translation initiation AUG codon and a frameshift that causes nonsense-mediated mRNA decay. Additionally, a large deletion has been described in an LFS family that removes 167 bp spanning part of exon 1 and intron 1 (Varley et al, 1997b). Although consequences of this deletion have not been reported, splicing is likely perturbed because the intron 1 splice donor site is eliminated by the deletion.…”

“…A ected probands and their relatives consented to participate in our Institutional Review Board-approved research protocol, release relevant medical records and donate blood samples for laboratory studies. (Varley et al, 1997b(Varley et al, , 1998b splice acceptor site site in exon 4 5…”

“…Outside this core region, deleterious p53 changes tend to be nonsense or frameshift mutations that cause premature protein translation termination (Ishioka et al, 1995;Hainaut et al, 1997;Beroud and Soussi, 1998;Sedlacek et al, 1998). In addition, mutations that cause alternate splicing of precursor mRNA have been described in six LFS kindreds (Warneford et al, 1992;Felix et al, 1993;Jolly et al, 1994;Frebourg et al, 1995;Varley et al, 1997bVarley et al, , 1998a. In this study we describe three additional LFS families with inherited p53 splice site mutations.…”

Li-Fraumeni syndrome – a molecular and clinical review

“…LOH has been seen in a number of benign or premalignant lesions, including ductal carcinoma in situ of the breast and endometrial hyperplasia (Varley et al, 1996a) and an adrenocortical tumour (Varley et al, 1995). More surprisingly, loss of the mutant allele has been seen in three cases Varley et al, 1997b).…”

“…This study by Li et al (1988) indicated that the spectrum of tumours within the syndrome included acute leukaemia, premenopausal breast carcinoma, brain and adrenocortical tumours as well as bone and soft-tissue sarcomas. Other studies have indicated that a number of other cancers may occur at an increased frequency in these families, notably melanoma, germ cell tumours, Wilms' tumours, gastric and pancreatic carcinomas and lung cancer (Hartley et al, 1987; 1989; Varley et al, 1995;1997a).…”