RB1 (RB transcriptional corepressor 1) is a tumor suppressor gene located on chromosome 13 that functions as a negative regulator of cell cycle progression and transcription. The protein acts as a transcriptional repressor by binding E2F1 and other transcription factors, thereby controlling the G1/S cell cycle checkpoint 1. RB1 regulates chromosome 13, heterochromatin formation, and mitotic progression through interactions with cyclin/CDK complexes and kinase binding [NCBI/GO annotations]. During viral infections, oncogenic proteins from SV40, HPV, and adenovirus disrupt the RB1-E2F1 complex, inactivating RB1's tumor suppressive function [UniProt]. RB1 mutations cause retinoblastoma, a pediatric eye malignancy requiring biallelic inactivation within retinal precursor cells 2. Germline RB1 mutations occur in 41.9% of retinoblastoma patients, with both small genetic rearrangements (78.9%) and large genomic rearrangements (21.1%) documented 3. Beyond retinoblastoma, concurrent RB1 and TP53 alterations identify high-risk EGFR-mutant lung cancers with 18% transformation to small cell carcinoma and significantly shortened survival (9.5 months vs. 36.6 months without dual mutations) 4. RB1 knockout in breast organoid models, combined with P53 and PTEN mutations, generates estrogen-receptor positive tumors responsive to endocrine therapy, supporting its role in multiple cancer subtypes 5. Genetic testing and counseling are essential for retinoblastoma patients to assess long-term malignancy risk and guide surveillance strategies.