Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma.

Abstract

We investigated the possibility that a proportion of children with sporadic rhabdomyosarcoma (RMS) carry constitutional mutations of the p53 tumor suppressor gene. 33 patients with sporadic RMS at two large outpatient pediatric oncology clinics submitted blood samples. Genomic DNA was extracted from peripheral blood leukocytes and PCR was used to amplify exons 2-11 of the p53 gene. Amplified genomic DNA was screened for the presence of germline p53 mutations using single-strand conformation polymorphism (SSCP) analysis. The DNA sequence of those samples that showed aberrant migration of bands on SSCP analysis was determined to identify the precise nature of the gene mutations. Patient records were reviewed to assess clinical correlates of the mutant p53 carrier state. Heterozygous constitutional mutations were detected in 3/33 patient samples screened. Two of these missense mutations are located in exon 7 and one in exon 8 of the p53 gene. The presence of mutations was not correlated with tumor histology, stage, or site. However, an association between young age at diagnosis and presence of a constitutional p53 mutation was noted: 3/13 children under the age of 3 yr at diagnosis carried mutations, whereas none of 20 children over 3 yr of age at diagnosis harbored a detectable constitutional mutation. These results in children with RMS corroborates previous findings in other clinical settings suggesting that the mutant p53 carrier state may predispose individuals to malignancy at an early age. Although this study did not assess whether the mutations were preexisting or new germline alterations, assessment of close relatives of RMS patients for cancer risk and predictive genetic testing may be indicated. (J. Clin. Invest. 1995Invest. . 95:1606Invest. -1611

Li-Fraumeni syndrome – a molecular and clinical review

“…In our series (Varley et al, 1997a), TP53 mutations have been detected in 71% of families with classic LFS, and it is possible that a high proportion of families with no detectable TP53 mutation have functional loss. Our data, together with those of other groups (Sameshima et al, 1992;Wagner et al, 1994;Diller et al, 1995) (Lustbader et al, 1992).…”

Sarcomas in TP53 germline mutation carriers

“…This estimate is compatible with the reported detection of a germline TP53 mutation in 4% to 9% of patients with early onset sarcoma (aged <45 years). [26][27][28] It follows that the risk of sarcoma before age 20 years may be up to 500 times higher in TP53 carriers compared with the risk in the general population. Our analysis indicates that the range of sarcoma types in TP53 mutation carriers is not covering the full range of sarcoma types that occur in the general population.…”

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

“…Over half of all families conforming to the de®nition of classic LFS and approximately one quarter of those which are Li ± Fraumeni-like (LFL, Birch et al, 1994) carry germline mutations to the TP53 gene (Malkin et al, 1990;Birch et al, 1994;Frebourg et al, 1995;Varley et al, 1997). Furthermore, a signi®cant proportion of patients with tumours which are typical of those seen in Li ± Fraumeni syndrome have also been shown to carry TP53 germline mutations at an increased frequency Sameshima et al, 1992;Toguchida et al, 1992;Brugieres et al, 1993;Kyritsis et al, 1994;McIntyre et al, 1994;Wagner et al, 1994;Chen et al, 1995;Diller et al, 1995;Li et al, 1995). TP53 is considered to be a tumour suppressor gene (Hollstein et al, 1991;Levine et al, 1991;Lane, 1992), and as such some tumours from patients with germline TP53 mutations have been analysed for loss of heterozygosity (LOH).…”