Radiotherapy and genetic susceptibility to cancer in a cohort of retinoblastoma patients

Purpose Survivors of hereditary retinoblastoma (Rb), a rare childhood cancer of the eye caused by germline mutations of the RB1 tumor suppressor gene, have an elevated risk of developing sarcomas, brain cancer or melanoma, but survivors with nonhereditary Rb, caused by somatic mutations in the RB1 gene, do not appear prone to secondary cancer. Because it is likely that the subsequent cancer risk in hereditary Rb continues throughout adult life, we have been studying a large cohort of Rb survivors to determine their risk of subsequent cancer and to evaluate the contribution of radiation and genetic susceptibility to this risk. Methods We extended the follow-up of a cohort of 1601 Rb survivors, diagnosed from 1914 to 1984 at two medical centers, to identify their risk of new cancers through 2000, compared with the expected number of cancers estimated from age-, sex-, and calendar year-specific from the Connecticut Tumor Registry. Results Subsequent cancer risk in 963 hereditary Rb patients (standardized incidence ratio SIR = 19, 95% confidence interval CI = 16–21) exceeded the risk in 638 sporadic RB patients (SIR = 1.2, 95% CI = 0.7–2.0). For hereditary Rb, the SIR was higher for those treated with radiation (SIR = 22, 95% CI = 19–24) versus those who were not (SIR = 6.9, 95% CI = 4.1–11). Among the hereditary Rb patients, significantly increased risks for cancers of the bone, soft tissue, brain, nasal cavities, and eye or orbit were likely related to radiation, which is consistent with previous findings. Newly identified risks possibly linked to radiation included cancers of the salivary gland, tongue, and breast. Excess risks for melanoma, and cancers of the lung, colon, and uterus in hereditary patients were unlikely to be associated with radiation in this cohort. Conclusion These data reveal a continuing increased cancer risk in hereditary but not nonhereditary Rb. Radiotherapy for hereditary Rb in early childhood continues to be associated with cancers in adulthood.