Clear cell renal cell carcinoma is frequently associated with mutation of which gene?

• A. BRCA2 mutation
• B. VHL mutation
• C. APC mutation
• D. MET mutation

Answer: (B)

In clear cell renal cell carcinoma, the most important idea is that loss of the VHL tumor suppressor gene drives the cancer. VHL normally helps mark HIF-α for destruction when oxygen levels are normal. When VHL is inactivated, HIF-α accumulates regardless of oxygen, turning on genes that promote blood vessel formation and tumor survival, especially VEGF. This makes the tumor highly vascular and explains why therapies that block the VEGF pathway are effective.

Other gene mutations listed don’t fit the typical pattern for clear cell RCC. BRCA2 is mainly linked to breast and ovarian cancer risk through DNA repair defects; APC is associated with colorectal polyposis and cancer; MET mutations are more characteristic of papillary RCC.