The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.

Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.

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 LiFraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-speci®c 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 50.02, 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 50.02 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-speci®c eects. Oncogene (2001) 20, 4621 ± 4628.

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Background-Neurofibromatosis type 2 (NF2) is a highly penetrant autosomal dominant condition predisposing aVected individuals to schwannomas and meningiomas. The proportion of children presenting with meningioma or schwannoma who have NF2 is not well described, and neither is the mode of presentation in most children with the inherited disease. Aims-To determine the frequency of childhood meningioma and schwannoma cases caused by NF2 and the mode of presentation. Methods-The records of the Manchester Children's Tumour Registry from 1954 were searched for cases of meningioma and schwannoma. Paediatric presentation in a large UK series of NF2 was also studied. Results-18% (61/334) of patients with NF2 on the UK database presented in the paediatric age group (0-15 years), frequently with the symptoms of an isolated tumour. More than half had no family history to alert the clinician to their susceptibility. Three of 22 children presenting with a meningioma on the Manchester Children's Tumour Registry have gone on to develop classic features of NF2. Conclusions-Clinicians should suspect NF2 in children presenting with meningioma, schwannoma, and skin features, such as neurofibromas/schwannomas, but fewer than 6 café au lait patches, who thus fall short of a diagnosis of neurofibromatosis type 1. (Arch Dis Child 1999;81:496-499)

The International Agency for Research on Cancer (IARC) is sponsoring a worldwide study of childhood cancer incidence. Cancers in children are highly specific and differ in many ways from cancers found in adults. Data for the international study will be presented according to the classification scheme described below which has been devised specifically for use with paediatric cancers. The features of this scheme are: (1) it is based on the International Classification of Diseases for Oncology (ICD-O); (2) diagnostic groups are defined mainly in terms of morphology; (3) the common types of childhood cancer are individually specified; (4) certain other rare conditions of interest are distinguished; (5) it provides for flexibility of data presentation with respect to amount of detail; (6) all possible combinations of ICD-O morphology and topography codes are included; and (7) the maximum number of codes has been allocated to specific categories. There is a great need for standardization in the classification of childhood cancers and we propose that the scheme be used for presentation of incidence data for results of aetiological and other related studies of cancer in children.

There is a significantly increased risk of second nervous system tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in childhood. Thus radiotherapy should only be used if absolutely essential in children with NF1.

We have analyzed a panel of 14 cases of childhood adrenocortical tumors unselected for family history and have identified germline TP53 mutations in >80%, making this the highest known incidence of a germline mutation in a tumor-suppressor gene in any cancer. The spectrum of germline TP53 mutations detected is remarkably limited. Analysis of tumor tissue for loss of constitutional heterozygosity, with respect to the germline mutant allele and the occurrence of other somatic TP53 mutations, indicates complex sequences of genetic events in a number of tumors. None of the families had cancer histories that conformed to the criteria for Li-Fraumeni syndrome, but, in some families, we were able to demonstrate that the mutation had been inherited. In these families there were gene carriers unaffected in their 40s and 50s, and there were others with relatively late-onset cancers. These data provide evidence that certain TP53 alleles confer relatively low penetrance for predisposition to the development of cancer, and they imply that deleterious TP53 mutations may be more frequent in the population than has been estimated previously. Our findings have considerable implications for the clinical management of children with andrenocortical tumors and their parents, in terms of both genetic testing and the early detection and treatment of tumors.