Chapter 7 . 1 Summary

Chapter 1 provides a general introduction to the Li-Fraumeni syndrome. Frederic P. Li and Joseph F. Fraumeni studied the possible association between childhood-onset sarcoma and breast cancer, after the referral of two cousins who both developed rhabdomyosarcoma in childhood. Subsequently, Li and Fraumeni suggested the existence of a new familial cancer syndrome with a predisposition to sarcoma, breast cancer, brain tumour, adrenal cortical carcinoma and leukaemia. In literature, various clinical criteria for Li-Fraumeni Syndrome (LFS) have been proposed, as listed in Table 1. LFS patients are at risk for multiple primary tumours: about 27%-50% of LFS patients develop a second primary tumour. In 1990 germline TP53 mutations were found in LFS kindreds and DNA analysis became available. Because germline TP53 mutations were also detected in families not fulfilling the LFS criteria, less stringent criteria for " Li-Fraumeni-like " (LFL) syndrome were defined. The LFL criteria were also based on the familial occurrence of cancer and included three affected family members. Subsequently, in 2001, Chompret et al. defined a novel set of criteria, updated in 2009, that included indications for TP53 analysis in sporadic cancer patients. Table 1 gives an overview of the LFS, LFL, Chompret en revised Chompret criteria. According to the literature, about 75% of LFS families, 40% of LFL families and 30% of families fulfilling the 2001 Chompret criteria carried pathogenic TP53 germline mutations. Currently, 423 TP53 germline mutations have been identified in the IARC mutation database (http://www-p53.iarc.fr/). The proportion of de novo TP53 germline mutations is between 7 and 24%. Since not all LFS or LFL families carry a TP53 germline mutation, other LFS candidate genes have been considered, but at present no alternative LFS genes have been identified. In TP53 mutation carriers the life time cancer risk is estimated to be 68%-100%; for women the risk is higher than for men. Management of TP53 mutation carriers remains a difficult issue, due to the different tumour sites and types of cancer involved and the variable ages of onset. In addition, for most LFS/LFL tumour types early detection and treatment are not available. Breast cancer surveillance is recommended for all female mutation carriers. It is still controversial whether mammography should be avoided due to increased radiosensitivity of TP53 germline mutation carriers. An annual clinical review and abdominal ultrasound during childhood are advised by some authors, surveillance can be recommended according to the familial phenotype (Chapter 5.1). The aims …