Genotype and phenotype in carriers of germline TP53 mutations

Abstract

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.