In The Netherlands, retinoblastoma patients have been registered in the Utrecht national retinoblastoma registry since 1862. This register is virtually complete from 1945 onwards. We describe a unique epidemiological survey of the occurrence of non-ocular cancer in all patients registered during the period 1945-1970. The occurrence of non-ocular cancer in relatives of patients with hereditary retinoblastoma is also reported. One hundred and forty-one patients with hereditary retinoblastoma were studied for non-ocular second primary cancer. Nineteen patients died of retinoblastoma. The median follow-up of the surviving 122 patients was 25 years. Seventeen of these patients developed a second primary cancer, most frequently soft-tissue sarcoma. The cumulative incidence of non-ocular cancer was 19% at the age of 35, i.e., a 14-fold increase as compared to the general population. Twelve patients with hereditary retinoblastoma died of non-ocular cancer whereas none of 252 patients with non-hereditary retinoblastoma died of non-ocular cancer. Furthermore, among the parents of our hereditary retinoblastoma patients, 24 (born before 1945) had also been affected by retinoblastoma or had affected sibs. In the parents, 4 tumors occurred, of which 2 were rhabdomyosarcomas and 2 were urinary bladder cancers. Both types of non-ocular cancer were also encountered among the 122 patients with hereditary retinoblastoma. In 103 fathers and 103 mothers of patients with hereditary retinoblastoma who did not have retinoblastoma themselves, there was no previous family history of retinoblastoma. The fathers had a relative risk of 8.3 for pancreatic cancer compared to the general population. There was no significant increase in the number of non-ocular tumors in 332 sibs of patients with hereditary retinoblastoma.
The influence of early diagnosis on sight and survival was studied in 130 patients with bilateral retinoblastoma. Nineteen patients died of this condition. Statistical analysis predicted that 12 of these 19 early deaths could have been prevented if doctors' delay had been less than 1 week. Consequently, a reduction of 65% in mortality is possible. Similarly, statistical analysis also predicted that the number of patients with resulting blindness could be reduced by 40%. Central registration and monitoring of retinoblastoma families would greatly improve early diagnosis.
An epidemiological survey has been carried out to establish the incidence of second malignant neoplasms in hereditary retinoblastoma survivors in The Netherlands and the relative risk of cancer in non-affected relatives. The cumulative incidence of second neoplasms was 19% at the age of 35 years. Fathers, unaffected by retinoblastoma, were at risk for pancreatic cancer, the relative risk being 8.3.
The importance of mutations in carcinogenesis is still unclear. Assuming that mutations of the genetic material are central to this problem, the number needed to give rise to a cancer cell must be established. A one-mutation theory is unsatisfactory for a number of reasons. A four-mutation model fits better and can be calculated in humans assuming that the observed endogenous tumors in 2% of the population equals the frequency of spontaneous carcinogenesis, accepting a mean mutation rate of 2 X 10(-5) mutations per gene per generation, and a production of about 7 X 10(15) cells during our whole lifetime. This model is also consistent with the observed peak incidence of cancer in children, with the hereditary aspects of some pediatric tumors, and with the usually nonhereditary mechanisms of cancer in adults.
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