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Li-Fraumeni syndrome is a rare autosomal dominant cancer predisposition syndrome characterized by a broad spectrum of tumors. The disorder is caused by germline mutations in the TP53 gene. We studied chromosomes in the sperm of two male carriers of TP53 mutations. We observed increased sperm aneuploidy, mainly concerning the gonosomes when compared to four normal male controls. This observation may correlate with the involvement of the p53 protein in spermatogenesis, with its role in aneuploidy in cancer, and with the occurrence of two cases of Turner syndrome in families with germline TP53 mutations reported in the literature., (2011 Elsevier Inc. All rights reserved.)

Background: A decrease in the age at cancer onset and increase in cancer incidence in successive generations in Li-Fraumeni syndrome (LFS) families with germline TP53 mutations have been previously described. In the current study a possible relation was analyzed between telomere length and cancer onset in TP53 mutation carriers., Methods: Telomere length was measured using real-time quantitative polymerase chain reaction (PCR) in 20 carriers of germline TP53 mutations and in 83 unrelated healthy individuals. According to the age at blood sampling, patients and controls were divided into 2 age groups, children and adults. Telomere length was correlated to TP53 mutation status and telomere shortening in patients to the age at cancer onset. A t-test and linear regression were used to analyze the data., Results: Compared with healthy controls, telomere length was significantly shorter both in the child (P = .001) and adult (P = .034) germline T53 mutation carriers. Although a statistically significant correlation between telomere shortening and the age at cancer onset was not observed, there was a trend of shorter telomeres in mutation carriers affected in childhood compared with those affected later in life. Neither cancer therapy nor sex differences were likely to affect the results., Conclusions: The findings suggest a possible link between the carriership of a germline TP53 mutation, telomere length, predisposition to early-onset cancer, and anticipation in LFS., ((c) 2007 American Cancer Society.)

We identified a missense germline mutation (Gly245Ser) in one of the mutation hot spots of the TP53 gene in two affected members of a Li-Fraumeni syndrome family. We also analyzed their tumors, a liposarcoma and a colorectal carcinoma. Both tumors exhibited p53 protein accumulation but none of them showed loss of the wild-type allele of the TP53 gene. We reviewed all published cases of tumors in germline TP53 mutation carriers where loss of heterozygosity data were available and identified 84 tumors with loss of the wild-type allele, 57 tumors with retention of heterozygosity, and 9 tumors with loss of the allele harboring the germline mutation. Among the tumors showing p53 accumulation, we observed a significant difference in the fraction of tumors showing p53 protein accumulation between the tumors with loss of the wild-type allele and those with retention of TP53 heterozygosity. This supports the idea that the pathogenesis of tumors in germline TP53 mutation carriers does not have to be associated with loss of the wild-type TP53 allele. The product of the normal allele can potentially be inactivated by a variety of other mechanisms or, as suggested by the analysis, many of these tumors may even preserve the activity of the wild-type p53 protein.

Anticipation in the age at onset of cancer in successive generations was described in several familial cancer syndromes. Based on multiple statistical analyses of a database of families with germline TP53 mutations, and using several different approaches and measures to eliminate possible biases, we show that anticipation may be a feature of the Li-Fraumeni syndrome. Definitive proof of anticipation in pedigrees with germline TP53 mutations will require more family data and further analysis, as well as research on the role of the p53 protein in processes like genome stability, which may represent the biological basis of anticipation in these families. This should have important practical implications for genetic testing, counselling, and preventative care for individuals at risk.