Sarcomas in hereditary retinoblastoma

Children diagnosed with the hereditary form of retinoblastoma (Rb), a rare eye cancer caused by a germline mutation in the RB1 tumor suppressor gene, have excellent survival, but face an increased risk for the development of sarcomas, both soft tissue (STS) and bone. This predisposition to sarcomas in retinoblastoma survivors has been attributed to genetic susceptibility as well as past radiation treatment for Rb.Retinoblastoma is a rare pediatric cancer of the eye with an autosomal dominant inheritance pattern. It is caused by mutations in the RB1 tumor suppressor gene, located on chromosome 13q14 with very high penetrance and expressivity [1]. Approximately 80%-90% of RB1 gene carriers develop ocular tumors. This gene encodes the cell cycle regulatory retinoblastoma gene protein (pRb), controls cellular differentiation during both embryogenesis and in adult tissues, regulates apoptotic cell death, maintains cell cycle arrest and preserves chromosome stability [2].Retinoblastoma occurs in two forms: hereditary (30-40%) and non-hereditary (60-70%). Hereditary retinoblastoma is caused by a germline mutation in one allele of the RB1 gene and an acquired somatic mutation in the other allele, whereas the non-hereditary form is caused by somatic mutations in both alleles. The hereditary form is characterized by disease in both eyes (bilateral Rb) and is typically diagnosed before 12？months of age, whereas, the non-hereditary form affects one eye (unilateral Rb) and is diagnosed between 2–5？years of age. About 10-15% of patients with unilateral Rb, however, carry a germline mutation and are considered hereditary. This difference in diagnosis age led Knudson to develop the two-hit theory [3], in which only one additional mutation is needed for hereditary Rb and two hits or somatic mutations are needed for non-hereditary Rb [4]. The age-adjusted annual incidence rate of retinoblastoma is 3.1 per 107 with a 5-year relative survival of 97.5% in the U.S. [5]. Treatment for Rb