Germline TP53 Mutation Carriers Research Articles

The single-nucleotide polymorphism 309 in the MDM2 gene contributes to the Li–Fraumeni syndrome and related phenotypes

Li-Fraumeni syndrome (LFS) is an autosomal-dominant cancer predisposition syndrome of which the majority is caused by TP53 germline mutations and is characterised by different tumour types occurring at relatively young age. Recently, it was shown that a single-nucleotide polymorphism (SNP) in the MDM2 gene, SNP309 (T>G variation), was associated with accelerated tumour formation in LFS patients who carry a TP53 germline mutation. To confirm this finding in different populations, we screened 25 Dutch and 11 Finnish TP53 mutation carriers for the presence of the SNP309 G allele in the MDM2 gene. Additionally, we investigated whether the SNP309 G allele plays a role in 72 Dutch TP53-negative LFS and LFS-related patients. In the TP53 germline mutation carriers, a significant difference was seen in the mean age of tumour onset for the SNP309 G allele group, that is, 29.7 years as compared to the SNP309 homozygous T group 45.5 years (P=0.005). In patients of LFS and LFS-related TP53-negative families, no difference was seen in the mean age of tumour onset. However, this TP53-negative group did show a significantly higher percentage of SNP309 homozygotes (G/G) compared to the general population (P=0.02). In conclusion, TP53 germline mutation carriers who have an SNP309 G allele have an earlier onset of tumour formation. The higher prevalence of MDM2 SNP309 homozygous G/G carriers in the TP53-negative group suggests that this allele contributes to cancer susceptibility in LFS and LFS-related families.

A Li-Fraumeni syndrome family with retained heterozygosity for a germline TP53 mutation in two tumors

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.

Relative frequency and morphology of cancers in carriers of germline TP53 mutations.

The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values <0.02, were designated strongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocortical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas was moderately associated. Leukaemia and neuroblastoma were weakly associated. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.

Genotype and phenotype in carriers of germline TP53 mutations

We collected data on a large cohort of families with features of Li-Fraumeni syndrome (LFS). To date we have identified germline TP53 mutations in 28 families: 20 of 25 classic LFS and 8 of 20 Li-Fraumeni−like. In addition we have identified germline mutations in 12 other individuals or families with tumors suggestive of LFS. Most mutations are missense or nonsense, but 7 (18%) are splicing mutations. A survey of the literature showed that this is a considerably higher proportion than has been identified by other groups. The proportion of germline TP53 splicing mutations in LFS families may be markedly under-reported. We have examined the biological consequences of these mutations to determine the functional properties of the mutant p53 and to confirm that they are causative mutations. Previous studies have indicated that five main component tumors are associated with LFS: sarcomas, brain and breast tumors, leukemia and adrenocortical carcinoma. We have analyzed the observed incidence of cancers in first- and second-degree relatives of probands in comparison with that expected, on the basis of United Kingdom national cancer rates. The observed pattern of cancers in germline TP53 carriers was highly significantly different from that expected across all ages. Carcinoma of the breast, brain and spinal cord tumors, bone and soft-tissue sarcomas, adrenocortical carcinoma, Wilms tumor and malignant phyllodes tumors were all strongly associated with a germline TP53 mutation. Common carcinomas (such as lung, colorectal, bladder, prostate, cervix and ovarian) did not occur to excess. Germline TP53 mutations are associated with a subset of specific, mainly rare cancers.