Retinoblastoma and low level radiation.

The village of Seascale, near the Sellafield nuclear reprocessing plant, is best known in epidemiological circles for its longstanding high incidence ofmalignant disease in young people,' which has recently been confirmed as having persisted during 1984-90.2 Throughout, the excess has been largely accounted for by leukaemia and non-Hodgkin's lymphoma. No cases of retinoblastoma have been found in Seascale, but at least five cases have occurred in children whose mothers had lived there at some time during 1950 onwards. The maternal grandfathers of three of these children had worked at Sellafield.3 Three further cases have occurred among children born in Copeland, the county district that contains both Seascale and Sellafield, but whose mothers had never lived in Seascale; the father of one and the paternal grandfather of another had worked at Sellafield. Controversy continues over the possible causes of the excess of leukaemia and lymphoma in Seascale. Gardner and colleagues concluded that the excess was restricted to children of mothers who were resident in Seascale at the time of the birth,45 but Kinlen has recently shown that a similar excess exists among young people in Seascale who were born elsewhere.6 In their case-control study of young people in West Cumbria diagnosed during 1950-85 Gardner et al found that the excess occurred among children whose fathers had been exposed to high levels of radiation before the child was conceived and suggested that some cases may have resulted from paternal germ cell mutation.7 This does not, however, account for the excess among those born outside Seascale. Epidemiological evaluation of the apparent association of retinoblastoma with Seascale is, if anything, even more difficult. Retinoblastoma occurs in two forms. Hereditary retinoblastoma is nearly always bilateral and occurs in families in which there has been a germ cell mutation of the RB 1 gene; the pattern of inheritance resembles that of an autosomal dominant trait with about 90°/0 penetrance. About two thirds of hereditary cases arise from new and one third from old germ cell mutations.8 Non-hereditary retinoblastoma is caused by two mutations to a somatic cell and is invariably unilateral. One of the cases linked to Seascale is known to be hereditary.3 This was in a girl with no family history of retinoblastoma who developed bilateral tumours; she had a partial deletion of chromosome 13 including the RB1 gene locus, which was not present constitutionally in either parent and thus represents a new germ cell mutation. It seems likely that most of the remaining, unilateral cases are non-hereditary as probably under one in 10 cases of unilateral retinoblastoma is hereditary. At first sight it is puzzling that no case has been diagnosed among children who were themselves resident in Seascale, although the observed incidence among children of mothers who had previously lived there has been calculated to be about 20 times expected.9 Even if the risk was indeed 20 times that in the rest of Britain, 0 only one case of retinoblastoma would be expected in Seascale every 40 years. Virtually nothing is known about the causes of nonhereditary retinoblastoma or of mutations leading to the hereditary form. The cumulative incidence for combined hereditary and non-hereditary forms of the condition ranges from 45-60 cases per million among mainly white populations to about 100 per million in Nigeria and Uganda"'; the highest recorded rate, though based on only 11 cases, is 153 per million among Navajo of the southwestern United States.'2 Little international variation exists in rates of bilateral retinoblastoma, with cumulative rates generally of 15-25 cases per million, whereas the incidence of the unilateral, predominantly non-hereditary form ranges from 30-40 cases per million in many industrialised nations with temperate climates to about 75 per million in tropical Africa"' and 125 per million among the Navajo.'2 These data indicate that non-hereditary retinoblastoma is more common among populations of low socioeconomic status and in tropical climates. The only published case-control study of retinoblastoma included 67 sporadic hereditary and 1 15 non-hereditary cases in North America.'3 There was a significantly raised odds ratio for non-hereditary tumours among children whose mothers had never attended high school, again pointing towards an association with poor socioeconomic conditions. Seascale, however, has a population of an unusually high socioeconomic status. Antenatal obstetric irradiation is the only environmental factor certain to cause more than a handful of cases of childhood cancer in Britain. By far the largest body of evidence for this is the Oxford survey of childhood cancers,"4 but separate analyses of retinoblastoma in the survey have never been published and, as cases were ascertained from death certificates and survival with retinoblastoma has been very high for at least half a century, it contains very few cases of this tumour. In the American study, for sporadic hereditary cases there was a non-significant increased odds ratio associated with preconceptional gonadal exposure to x rays in either parent, while for non-hereditary cases there was a non-significant raised risk with exposure to x rays during pregnancy.13 Many Navajo have been engaged in uranium mining, but information on exposure to ionising radiation was apparently not available for the affected Navajo children or their parents. A large study linking the records of the National Registry of Childhood Tumours with those of the National Registry of Radiation Workers is in progress, and this should show whether there is a raised risk of childhood cancer in general, or of particular types, in the offspring of radiation workers and, if so, whether the risk is related to the dose of radiation."5 The best available method for moving closer to solving this puzzle may be to study DNA from the affected children, as this might distinguish somatic from germ line mutations.3 If a mutation could be found in tumour material this would lead to a search for constitutional mutations in the child and his or her parents. Ifgerm line mutations are found the type of mutation might shed light on their cause.