Summary In a series of 882 retinoblastoma patients, 384 known to have the genetic form of the disease and 498 others, 30 patients developed second primary neoplasms. The spectrum of these second neoplasms is discussed in relation to the forms of treatment used for the retinoblastoma. Cumulative incidence rates of second tumours in the whole series are 2.0% at 12 years after diagnosis and 4.2% after 18 years. For patients with the genetic form of retinoblastoma the cumulative incidence rate after 18 years is 8.4% for all second neoplasms and 6.0% for osteosarcomas alone. The inherent risk among survivors from genetic retinoblastoma of developing an osteosarcoma, excluding all possible effects of treatment, is estimated to be 2.2% after 18 years. Within the field of radiation treatment the cumulative incidence rate for all second neoplasms after 18 years is 6.6% and for osteosarcomas alone 3.7%. There is some evidence that patients with genetic retinoblastoma are particularly sensitive to the carcinogenic effects of radiation. The results also suggest that the use of cyclophosphamide may increase the risk of second primary neoplasms in patients with genetic retinoblastoma. The incidence rates of second primary neoplasms in retinoblastoma survivors reported here are lower than those quoted for previously published series. Evidence from this and other papers strongly suggests an association between retinoblastoma and malignant melanoma.

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A registry including information about nearly 1,600 cases of retinoblastoma diagnosed in Britain has been created at the Childhood Cancer Research Group. Cases have been classified as 'old germ cell mutation', 'new germ cell mutation' or 'sporadic non-hereditary'. For a population-based group of 918 cases diagnosed between 1962 and 1985 we have calculated the proportions of unilateral/bilateral and hereditary/non-hereditary cases. Bilateral cases represent 40% of the total number over this period; the proportion known to be hereditary is 44%, a higher proportion than has been reported elsewhere. By following up selected groups of cases, an estimate has been made of the proportions of siblings of retinoblastoma patients and offspring of survivors from retinoblastoma who are themselves affected with the disease. Where there is no previous family history, the risk for siblings of retinoblastoma patients of developing the disease is approximately 2% if the disease in the affected child is bilateral and 1% if it is unilateral, assuming that there are no other siblings; if there are unaffected siblings the risks for subsequent children are lower. Children of patients with hereditary retinoblastoma have a one in two chance of carrying the germ cell mutation and for those who are carriers the probability of developing retinoblastoma is very close to the accepted figure of 90% if the parents have bilateral retinoblastoma but probably less if they have the unilateral form. For children of patients not known to be carriers, the probability of developing retinoblastoma is estimated to be about 1%, considerably lower than the previously accepted figure of about 5%. Retinoblastoma kindreds consist mainly of bilateral cases but there is evidence that some kindreds have a high proportion of unilateral cases. The ways in which these findings may be used in conjunction with modern techniques of molecular biology for prenatal and postnatal genetic counselling are discussed.

Summary A series of 1,438 parents and 2,663 other relatives of retinoblastoma patients have been followed up to ascertain the incidence among them of non-ocular cancer. Among 117 of these relatives who were known carriers of the mutation of the retinoblastoma gene 23 cases of non-ocular cancer developed during the follow-up period of the study. This compares with an expected number of 2.3, a relative risk of 9.9. A total of 25 deaths among these carriers included 21 from non-ocular cancer; the expected number was 1. 8

Summary The National Registry of Childhood Tumours contains over 51 000 records of children born in Great Britain who developed cancer under the age of 15 years. Patterns of childhood cancer among families containing more than one child with cancer have been studied. A total of 225 'sib pair' families have been ascertained from interviews with parents of affected children, from hospital and general practitioner records and from manual and computer searches of names and addresses of patients. A number of special groups have been identified, including those with a known genetic aetiology such as retinoblastoma, twins and families with three or more affected children. A further 148 families not in any of the above groups contain two children with cancer: in 46 families the children had tumours of the same type, most commonly leukaemia. Some of the families are examples of the Li-Fraumeni syndrome; some are associated with other conditions, including Down's syndrome. There is clearly a genetic element in the aetiology of cancer in some families discussed here; shared exposure to environmental causes may account for others and some will be simply due to chance.