In Wilms tumor (nephroblastoma), which molecular mechanism underlies loss of WT1 tumor suppressor function in the most common sporadic form?
- A Chromosomal translocation creating a fusion oncoprotein that antagonizes WT1 DNA binding
- B Biallelic inactivation through point mutation of one allele and loss of heterozygosity at 11p13 affecting the second allele ✓
- C Promoter hypomethylation causing overexpression of a WT1 dominant-negative isoform
- D microRNA-induced translational repression of WT1 mRNA without genomic alterations
Correct answer: B. Biallelic inactivation through point mutation of one allele and loss of heterozygosity at 11p13 affecting the second allele
Explanation
WT1, located at chromosome 11p13, follows the Knudson two-hit model. In sporadic Wilms tumor, the first hit is typically a point mutation in one WT1 allele in a renal progenitor cell; the second hit is loss of heterozygosity at 11p13 (somatic deletion or mitotic recombination), eliminating the remaining wild-type allele. WT1 normally acts as a transcription factor repressing growth-promoting genes (e.g., IGF2) and promoting nephrogenic differentiation; loss allows persistent growth of metanephric blastema cells.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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