All of the following are examples of oncogenes activated by chromosomal translocation EXCEPT:

## Oncogene Activation by Chromosomal Translocation **Key Point:** Chromosomal translocations can activate oncogenes by creating abnormal fusion proteins or placing proto-oncogenes under control of strong promoters. BRCA1 is a **tumor suppressor**, not an oncogene, and is inactivated through loss of heterozygosity — not translocation-mediated activation. ### Mechanism of Translocation-Mediated Oncogene Activation Translocations activate oncogenes through two main mechanisms: 1. **Fusion protein formation:** Two genes fuse to create a chimeric protein with abnormal function 2. **Promoter juxtaposition:** Oncogene placed under control of a strong constitutive promoter (e.g., immunoglobulin, T-cell receptor) ### Examples of Translocation-Activated Oncogenes | Translocation | Fusion Protein | Cancer | Mechanism | | --- | --- | --- | --- | | t(9;22) | BCR-ABL | CML | Fusion protein with constitutive tyrosine kinase activity | | t(8;14) | MYC-IGH | Burkitt lymphoma | MYC placed under IGH promoter; constitutive overexpression | | t(15;17) | PML-RARA | APL | Fusion protein blocks differentiation; sensitive to ATRA | | t(12;21) | ETV6-RUNX1 | Pediatric ALL | Fusion transcription factor | | t(11;22) | EWS-FLI1 | Ewing sarcoma | Fusion transcription factor | **High-Yield:** BCR-ABL, MYC-IGH, and PML-RARA are classic examples of translocation-activated oncogenes tested in NEET PG. ### BRCA1: Tumor Suppressor, Not Oncogene **Key Point:** BRCA1 is a **tumor suppressor gene** that encodes a DNA repair protein. It is inactivated in hereditary breast cancer through: - Loss of heterozygosity (LOH) - Point mutations - Epigenetic silencing BRCA1 is NOT activated by translocation and does NOT function as an oncogene. Its loss removes a brake on cell division, allowing transformation — this is the opposite of oncogene activation. **Clinical Pearl:** BRCA1 mutations follow the **two-hit hypothesis** (Knudson): germline mutation in one allele, somatic loss of the second allele in target tissue. This is characteristic of tumor suppressors, not oncogenes. **Mnemonic:** **Oncogenes = Gas pedal** (activated by translocation, amplification, mutation); **Tumor suppressors = Brakes** (inactivated by loss, mutation, epigenetic silencing). BRCA1 is a brake. [cite:Robbins 10e Ch 7]