Which tumor suppressor gene is the most commonly inactivated in human malignancies?

Explanation

## Most Commonly Inactivated Tumor Suppressor Gene **Key Point:** TP53 (p53) is inactivated in >50% of all human cancers, making it the most frequently altered tumor suppressor gene across all malignancy types. ### TP53 — The "Guardian of the Genome" **High-Yield:** TP53 mutations are found in: - Lung cancer: ~50% - Colorectal cancer: ~50–70% - Breast cancer: ~20–30% - Hepatocellular carcinoma: ~30–50% - Ovarian cancer: ~50% - Li-Fraumeni syndrome (germline TP53 mutations): 100% cancer predisposition ### Comparison of Major Tumor Suppressors | Gene | Chromosome | Most Common Cancer | Frequency of Inactivation | Function | | --- | --- | --- | --- | --- | | **TP53** | 17p13 | Lung, colon, breast | >50% of all cancers | Cell cycle arrest, apoptosis, DNA repair | | RB1 | 13q14 | Retinoblastoma, lung | ~15% of cancers | G1/S checkpoint control | | BRCA1 | 17q21 | Breast, ovarian | 5–10% of breast cancers | DNA repair (homologous recombination) | | APC | 5q21 | Colorectal | 80% of colorectal cancers | Wnt pathway regulation, cell adhesion | **Clinical Pearl:** While APC is inactivated in 80% of colorectal cancers, it is NOT the most common across all cancer types globally. TP53 remains the most universally altered. **Mnemonic:** **"P53 is PRESENT in >50% of cancers"** — P = Present everywhere, 53 = TP53, 50% = frequency. ### Mechanism of TP53 Loss 1. Point mutations (most common) 2. Deletions of 17p (loss of heterozygosity) 3. MDM2 amplification (negative regulator of p53) 4. HPV E6 protein binding (inactivates p53 in cervical cancer) **Warning:** Do not confuse frequency of inactivation with frequency in a single cancer type. APC is more commonly mutated in colorectal cancer specifically, but TP53 is more common across all malignancies.