Sensitivity and predictive value of criteria for p53 germline mutation screening

EDITOR—The history of Li-Fraumeni syndrome (LFS) is a good illustration of the delineation of dominantly inherited family cancer syndromes. The identification of this syndrome is the result of the combination of two kinds of evidence, firstly, a number of reports on particular familial aggregations 2 and, secondly, systematic family studies of childhood sarcomas. Among these studies, the decisive contribution came from Li and Fraumeni who were the first to publish the results of a family study on 641 children with rhabdomyosarcoma which led to the identification of four families in which a sib or a cousin was aVected by rhabdomyosarcoma or another soft tissue sarcoma (STS). These families also had several members who were aVected by diverse types of malignant tumours, in particular sarcomas and breast cancer at a very young age. This prompted the authors to propose the existence of a new familial syndrome. A prospective study on these families over 12 years provided evidence of a strong predisposition to cancer with a strikingly high frequency of multiple tumours. The term “Li-Fraumeni syndrome” was used for the first time in 1982 and the criteria, which subsequently became the classical definition of the syndrome, were proposed by Li and Fraumeni in 1988. These were a proband with a sarcoma before 45 years of age, a first degree relative with cancer before this age, and another close (first or second degree) relative in the lineage with either cancer before this age or a sarcoma at any age. These criteria led to the selection of 24 families which exhibited a wide variety of tumours including bone sarcomas, STS, breast cancer, brain tumours, leukaemia, adrenocortical carcinoma, lymphoma, lung, stomach, pancreas, and prostate cancer, but only the first six types were significantly in excess of the expected proportion among subjects aVected by cancer before 45 years in the American population. The follow up of these families confirmed an unusually high predisposition to cancer. Other studies have indicated that a number of other cancers may occur in these families, the most notable being melanoma, germ cell tumours, gastric carcinoma, and Wilms’ tumour. 12–16 The definition of the syndrome shifted from clinical and familial criteria to molecular criteria after Malkin et al and Srivastava et al described the involvement of germline p53 mutations. The mutations initially found were all missense mutations of exon 7, but further studies, extensively reported by Varley et al showed that other regions might also be involved. Studies on series of families with the classical LFS criteria showed that 50 to 70% of these families displayed a p53 mutation, indicating that mutation screening may have overlooked alterations that aVect regulatory regions and not p53 coding sequences or that germline mutation of other gene(s) may be responsible for LFS. Indeed, the study recently published by Bell et al showed that heterozygous germline mutations in hCHK2 occur in LFS. The proportions of p53 mutations are somewhat lower when less stringent criteria are applied. 21 After ascribing LFS to germline p53 mutations, diVerent studies were conducted on series of patients with tumours typifying LFS, but not selected on family history, to determine the proportion of gene carriers among them. The studies on patients with bone sarcoma or STS showed that up to a third of the group with early onset, an unusual family history, or multiple primary tumours may be carriers. Children with adrenocortical carcinoma were found to have the highest rate (50-80%). 31 The frequency of mutations among patients with multiple primary tumours was estimated to be between 7 and 20%. Far lower rates were found for patients with brain tumours, or early onset/familial breast cancer, although the breast cancer risk was clearly high in p53 mutation carriers. In some of these studies, a selection bias on family history may be suspected. Indeed, a significant proportion of mutations were found among cases with a strong positive family history, the frequency of which appeared to be unusually high. None of these studies allowed an estimation of cancer risk in mutation carriers, although unaVected carrier relatives are found in family studies. Indeed, LFS selection criteria are so stringent that it is impossible to correct for selection bias. Even looser criteria, such as Li-Fraumenilike 44 (LFL) or Li-Fraumeni incomplete (LFI) do not allow correction for ascertainment bias. This was the reason that we undertook a study at the Institut Gustave Roussy with very loose criteria which oVered two advantages: (1) they did not imply the existence of highly penetrant susceptibility genes and therefore potentially allowed the detection of mutations associated with a low cancer risk; (2) correction for selection bias was possible for the estimation of cancer risks in individual subjects. Our main conclusions are: (1) that cancer risks are very high, (2) although unaVected carriers may be observed, there is no evidence for the existence of mutations with particularly low penetrance, and (3) the proportion of de novo mutations is probably substantial. While the above mentioned were gradually defining with ever greater accuracy the relationship between constitutional mutations and cancer types and risks, an international multidisciplinary group was trying to establish recommendations for predictive testing. 46–50 For such testing, it was essential, as a first step, to evaluate individual and familial criteria to undertake the initial search in a family, in terms of sensitivity and predictive value. We report here the results obtained from our study on childhood cancer at the Institut Gustave Roussy and on a study of breast cancer in very young women performed at the Institut Curie in France. The family history of cancer in children under 18 years treated for all types of solid malignant tumours in the Department of Paediatric Oncology at the Institut Gustave Roussy in Villejuif (France) was investigated between January 1991 and May 1997. Information was collected through a direct interview with a trained counsellor for families of patients treated in the department during the study period. Information was obtained via a mailed questionnaire and completed in most cases by a telephone interview for patients treated before that period and no longer followed up or who had died. To minimise possible biases owing to genetic and environmental heterogeneity, only white children were included in the study. Family data were collected through the proband’s parents. They included information on each of the proband’s first and second degree relatives and first cousins. When necessary, additional family members, Letters 43