## Why Loss of chromosome 3p with VHL gene inactivation is right The structure marked **A** is Clear Cell RCC, the most common subtype (~75% of all RCCs). The hallmark genetic lesion is inactivation of the VHL (von Hippel-Lindau) tumor suppressor gene located on chromosome 3p25. In sporadic cases (~90%), this occurs through somatic loss of 3p combined with a second hit (mutation/methylation) on the remaining allele. In hereditary von Hippel-Lindau syndrome (autosomal dominant), a germline VHL mutation predisposes to bilateral/multifocal RCCs, hemangioblastomas, pheochromocytomas, and pancreatic cysts. VHL loss leads to accumulation of HIF-1α and HIF-2α, driving angiogenesis and the characteristic clear cell phenotype (glycogen and lipid accumulation). This is the single most important molecular driver of clear cell RCC pathogenesis (Robbins 10e Ch 20; Harrison 21e Ch 84). ## Why each distractor is wrong - **Translocation t(X;1) with PRCC-TFE3 fusion**: This is characteristic of Papillary RCC (subtype **B**), not Clear Cell RCC. This fusion is seen in Xp11 translocation RCC, a distinct entity. - **Mutations in FLCN gene on chromosome 17q**: FLCN mutations are associated with Birt-Hogg-Dubé syndrome, which predisposes to chromophobe RCC and oncocytoma, not clear cell RCC. - **Amplification of MET proto-oncogene on chromosome 7q**: MET alterations (mutations, amplification) are the hallmark of Papillary RCC (subtype **B**) and hereditary papillary RCC, not clear cell RCC. **High-Yield:** VHL loss → HIF accumulation → angiogenesis + clear cell phenotype; the "3p loss" is the molecular signature of clear cell RCC in both sporadic (somatic) and hereditary (germline) settings. [cite: Robbins 10e Ch 20; Harrison 21e Ch 84]
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