Abstract 1333: Specific RB1 mutations and risk of subsequent neoplasms among survivors of hereditary retinoblastoma.
Authors: Morton Lindsay M. , Wong Jeannette R. , Gallie Brenda L. , Abramson David H. , Seddon Johanna M. , Dean Michael , Gold Bert , Goldstein Alisa M. , Kleinerman Ruth A. , Tucker Margaret A. 
Published: August 2014

Abstract
The retinoblastoma tumor suppressor gene (RB1) is a key regulator of cell cycle control, most notably through E2F transcription factor binding. Deregulation of RB1 is important in many cancers. Survivors of hereditary retinoblastoma, caused by a germline mutation in RB1, experience substantially elevated risks for subsequent neoplasms, particularly bone and soft tissue sarcomas and melanomas. Oncogenic RB1 mutations arise from a range of DNA alterations and occur throughout the gene. No previous study has evaluated how the specific location and functional consequences of these RB1 mutations may differentially confer risk for specific subsequent neoplasms. As part of a biomarker study nested within a long-term follow-up study of the risk of subsequent cancers in retinoblastoma survivors, we identified germline RB1 mutations in 76/80 (95%) survivors of hereditary retinoblastoma who developed at least one subsequent neoplasm and had sufficient DNA for mutation testing (median follow-up time=47 years, range 7-71 years). Survivors were classified into four groups according to whether they ever developed a soft tissue sarcoma (STS, N=47), melanoma (without STS, N=10), bone tumor (without STS, N=5), or another type of subsequent malignant neoplasm (N=14). The identified mutations were distributed throughout RB1, from the promoter through exon 25. Nonsense, frameshift, or splice mutations that resulted in premature termination of the RB1 residue sequence were identified in 51 (67%) survivors, with the remaining classified as having loss of multiple exons (N=6), loss or rearrangement of a single exon (N=5), a splice mutation (N=7), a missense mutation (N=4), or an intronic substitution with unknown consequence (N=3). Preliminary analyses indicated that RB1 mutations resulting in loss of &gt;2 exons were more common in survivors with a subsequent STS (40/47, 85%) than those with a subsequent melanoma (6/10, 60%) or bone tumor (2/5, 40%; Fisher's exact P&lt;0.001). In an analysis of the RB1 regions impacted by the mutation, those that affected E2F binding (including mutations affecting the E2F binding site, Domain B, or Domain C) were more common in survivors with a subsequent STS (46/47, 98%) or melanoma (9/10, 90%) than those with a bone tumor (2/5, 40%; Fisher's exact P=0.020). Further analyses will include 14 additional survivors who developed a subsequent neoplasm for whom mutation testing is ongoing, and comparison of the spectrum of RB1 mutations in these survivors to hereditary retinoblastoma survivors without a subsequent neoplasm. If confirmed, such correlations between specific RB1 mutations and subsequent neoplasm risk may inform long-term surveillance practices for hereditary retinoblastoma survivors and provide insight into the key role of RB1 in oncogenesis.
Citation Format: Lindsay M. Morton, Jeannette R. Wong, Brenda L. Gallie, David H. Abramson, Johanna M. Seddon, Michael Dean, Bert Gold, Alisa M. Goldstein, Ruth A. Kleinerman, Margaret A. Tucker. Specific RB1 mutations and risk of subsequent neoplasms among survivors of hereditary retinoblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1333. doi:10.1158/1538-7445.AM2013-1333