Valerie Blair

Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome.

The Li–Fraumeni cancer predisposition syndrome is associated with germline TP53 mutations in the majority of families. We have investigated cancer incidence in 34 Li–Fraumeni families, according to their constitutional TP53 mutation status. Families with germline missense mutations in the core DNA binding domain showed a more highly penetrant cancer phenotype than families with other TP53 mutations or no mutation. Cancer phenotype in families carrying such mutations was characterized by a higher cancer incidence and earlier ages at diagnosis, especially of breast cancer and brain tumours, compared with families carrying protein truncating or other inactivating mutations (P=0.03 for all cancers, P=0.006 for breast cancers, P=0.05 for brain tumours). Proband cancers showed significantly younger ages at diagnosis in those with missense mutations in the DNA binding domain than in those with protein inactivating mutations (P=0.031). In individuals with the former type of mutation, there was a significantly lower proportion of tumours which showed loss of the wild-type TP53 allele (P=0.004). These results are consistent with observations in experimental systems which demonstrate that certain mutations exhibit gain of function and/or dominant-negative properties. Our results support an enhanced oncogenic potential for such mutations in human populations.

Improvements in survival from childhood cancer: results of a population based survey over 30 years

Survival from cancer of children whose cancer was diagnosed during the 30 years 1954-83 was analysed. The study was population based with nearly 3000 cases covering about 30 million child years at risk. When survival during the three decades 1954-63, 1964-73, and 1974-83 was compared striking improvements were observed. For all childhood cancer five year survival increased from 21% in the first decade to 49% in the third decade. During the first and third decades five year survival rates for acute lymphocytic leukaemia increased from 2% to 47%, Hodgkins disease from 44% to 91%, non-Hodgkins lymphoma from 18% to 45%, Wilmss tumour from 31% to 85%, and germ cell tumours from 10% to 64%. Twenty patients developed second primary tumours, but otherwise there were few late deaths. Less than 1% of children who survived without a relapse for 10 years subsequently died of their initial cancer. Survival from childhood cancer is no longer rare, and people who have been cured of cancer during childhood should be accepted as normal members of society.

The inter-regional epidemiological study of childhood cancer (IRESCC): case-control study of children with central nervous system tumours.

Tumours of the central nervous system comprise 23% of all childhood cancers and form the most common group of solid malignancies. Little is know about their aetiology. The present report concerns the results of a case-control study of 78 incident cases of central nervous system tumours in children. No case-control differences were detected for the following: pre-natal diagnostic X-rays, general anaesthetics during pregnancy, pregnancy infections, pregnancy drugs (including sedatives, tranquillizers and anti-convulsants), alcohol consumption in pregnancy, childs birthweight, breast-feeding, childhood illnesses, previous medication in the child. A significant excess of case mothers had suffered from diseases of the nervous system (RR 2.6). There was a deficit of children who had been immunised among the case children which approached significance, and an excess of congenital abnormalities among cases which also approached significance. There was a small excess of neoplastic disease among case parents. The results of this study suggest that in our patients genetic rather than environmental factors are more important, but the small numbers included in the present study meant that no definite conclusions could be reached.

Multiple lipomatosis and childhood cancer. A new association

Abstract The occurrence of multiple lipomatosis in the families of six children with malignancy is described and it is suggested that this may represent a new association.

The Epidemiology of Leukemia: Results from the Manchester Children’s Tumour Registry

The Manchester Children’s Tumour Registry gathers clinical and epidemiological information on all childhood cancers from a defined population base. Between 1954 and 1988 there were 1107 leukemias (879 ALL, 203 ANLL, 21 CML, and 4 other unspecified). The rates per 106 child years for ALL, ANLL, CML, and all leukemias were 26.2, 6.1, 0.6, and 33.1, respectively. Linear regression analyses of the annual incidence showed an upward trend in ALL, but this was not statistically significant. Comparison of ALL rates during 5–7 year periods (1954—1960, 1961–1967, 1968–1974, 1975–1981, 1982–1988) showed no significant differences among children aged <1, 5–9 and 10–14, but a significant increase in children aged 1–4. Rates were 41.8, 45.2, 53.1, 54.2, and 55.5 during each successive period, respectively (chi squared trend = 4.8, p < 0.05). In order to explore these time trends for ALL in more detail, 5-year running means of the annual incidence by age group were plotted. While in children aged <1, 5 –9 and 10–14 there was little apparent variation, the incidence pattern for the 1–4 year age group appeared to be cyclical, i.e., there were successive increases and decreases in incidence. This observation is compatible with the idea that in childhood common ALL the pattern of infections in early life may be etiologically important and a fluctuation in incidence may reflect fluctuations in the prevalence of infectious agents. The rates for ANLL were stable throughout the study period overall and within each age group.