## Why VHL gene mutation on chromosome 3p25 is right The structure marked **D** represents VHL gene mutation, which is the hallmark molecular abnormality in clear cell RCC. According to Harrison 21e Ch 88, VHL mutations occur in nearly all cases of clear cell RCC—both sporadic (~80%) and hereditary (VHL syndrome, autosomal dominant). The VHL gene is located on chromosome 3p25 and functions as a tumor suppressor. Loss of VHL function leads to accumulation of HIF (hypoxia-inducible factor), driving angiogenesis (explaining the delicate vascular network seen histologically) and lipid/glycogen accumulation in tumor cells (explaining the clear cytoplasm). This is the defining genetic feature of clear cell RCC. ## Why each distractor is wrong - **MET proto-oncogene mutation**: This is characteristic of papillary RCC type 1 (hereditary papillary RCC), not clear cell RCC. While papillary RCC is the second most common RCC subtype (~10-15%), it has a distinctly different histology and genetic basis. - **BHD gene mutation**: This is the hallmark of chromophobe RCC and Birt-Hogg-Dubé syndrome (associated with fibrofolliculomas, pneumothorax, and renal cancers). Chromophobe RCC represents only 5-10% of RCC cases and has different histological features from clear cell RCC. - **FH gene mutation**: This causes hereditary leiomyomatosis and RCC (HLRCC), associated with type 2 papillary RCC and cutaneous/uterine leiomyomas (Reed syndrome). This is not the genetic basis of clear cell RCC. **High-Yield:** VHL mutation → HIF accumulation → angiogenesis + lipid/glycogen → clear cell RCC histology; nearly all clear cell cases carry this mutation. [cite: Harrison 21e Ch 88]
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