Sarcomas after retinoblastoma: Role of genetic susceptibility and radiation dose

*Ruth Anne Kleinerman, National Cancer Institute 

Keywords: retinoblastoma, radiotherapy, sarcoma, genetic susceptibility

Long-term survivors of childhood hereditary retinoblastoma, caused by a germline mutation in the RB1 gene, are at a 20-fold increased risk of developing and dying from a subsequent non-ocular cancer, primarily bone and soft tissue sarcomas, melanoma and brain tumors (1,2). Survivors of non-hereditary retinoblastoma, caused by somatic mutations in the RB1 gene, are at much lower risk of a subsequent primary cancer, similar to the risk in the general population. Sarcomas account for almost half of the second primary cancers in hereditary retinoblastoma survivors. The risk for sarcomas in hereditary survivors has been attributed to genetic susceptibility due to inactivation of the RB1 gene and past treatment with radiation (3). The majority of sarcomas among hereditary retinoblastoma survivors have been diagnosed in the head area, within the radiation field, but a substantial portion of the bone sarcomas (up to 40 %) have also occurred outside the radiation field, mainly in the lower legs. In addition, 12-32% percent of the soft tissue sarcomas have been diagnosed outside the radiation field mainly in the trunk (4). Risk of bone and STS begins within 10 years of treatment for hereditary retinoblastoma and continues throughout adulthood. Radiation exposure, mainly high-dose, is one of the few identified risk factors for bone and soft tissue sarcomas (5). In a nested case-control study of sarcomas conducted within a large cohort of retinoblastoma survivors, individual radiation doses were estimated to the sites of the bone and soft tissue sarcomas for 67 cases and their 89 controls (6). The majority of hereditary retinoblastoma survivors in the cohort had been treated with external beam radiotherapy, and the average dose to the affected eye was 48 Gy (15-115 Gy). The doses to bone sarcoma sites in the radiation field ranged from 28-56 Gy for cases and 15-46 Gy for controls, however, the dose to the lower legs was <10 cGy for cases and controls. The doses to soft tissue sarcoma sites in the radiation field ranged from 24-45 Gy for cases and 12-36 Gy for controls. The risk for soft tissue sarcomas was significantly increased at 10 Gy and risk continued to be significantly increased up to 11.7 at =60 Gy compared to a referent group of less than 5 Gy. The risk for soft tissue and bone sarcomas combined, however, was significantly increased starting at 5-9 Gy and risk continued up to 10.7-fold at =60 Gy. The estimated EOR/Gy for bone and soft tissue sarcomas was 0.19 (95%CI=0.136-0.315) and the EOR/Gy for soft tissue sarcomas only was 0.166 (95%CI=0.25-16). The bone and soft tissue sarcomas occurring in the radiation field suggested an interactive effect between radiation and genetic susceptibility, whereas, genetic susceptibility was likely associated with the bone sarcomas occurring in the lower leg, because they received virtually no radiation. In addition to the epidemiologic evidence from the aforementioned case-control study, other cohort studies have reported a radiation dose-related risk for bone sarcomas in hereditary retinoblastoma survivors (7,8). Structural alterations of the RB1 gene have been well documented in both primary bone sarcomas (9) and soft tissue sarcomas (10). Recognition of the increased risk for sarcomas associated with past radiotherapy in hereditary retinoblastoma survivors has influenced the current treatment of retinoblastoma with a trend towards greater use of chemotherapy, focal therapies (laser or cryosurgery) and most recently, chemosurgery.

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