## Retinoblastoma Genetics **Key Point:** The RB1 gene (located on chromosome 13q14) is the primary tumor suppressor gene responsible for retinoblastoma development. Loss of function of this gene leads to uncontrolled proliferation of retinal cells. ### RB1 Gene Function The RB1 gene encodes the retinoblastoma protein (pRb), which acts as a critical checkpoint control in the G1/S phase of the cell cycle. When functional, pRb binds to E2F transcription factors and prevents progression from G1 to S phase. ### Inheritance Pattern - **Germline mutations (40% of cases):** Bilateral or multifocal disease; autosomal dominant inheritance with incomplete penetrance (~90%) and variable expressivity - **Somatic mutations (60% of cases):** Unilateral, unifocal disease; sporadic occurrence **High-Yield:** Approximately 90% of bilateral retinoblastoma cases have germline RB1 mutations, whereas only 15–20% of unilateral cases carry germline mutations. ### Two-Hit Hypothesis (Knudson) Retinoblastoma typically requires two inactivating events: 1. First hit: Inherited or somatic mutation in one RB1 allele 2. Second hit: Somatic mutation in the other allele (loss of heterozygosity) In hereditary cases, the first hit is present in all cells; the second hit occurs somatically in retinal cells, leading to tumor development. **Clinical Pearl:** Patients with germline RB1 mutations have increased risk of secondary malignancies (osteosarcoma, soft tissue sarcoma, melanoma) later in life, particularly in the radiation field if external beam radiotherapy is used. [cite:Robbins 10e Ch 17] 
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.