A 5-year-old boy from rural Maharashtra is brought to the pediatric oncology clinic with a large abdominal mass and hematuria. Imaging reveals a unilateral Wilms tumor (nephroblastoma) with no distant metastases. Genetic testing shows a heterozygous WT1 mutation. His father is phenotypically normal and does not carry the mutation. Which of the following best describes the genetic basis of this tumor and the expected molecular events?

Explanation

## WT1 and Wilms Tumor: Two-Hit Model ### Genetic Basis: De Novo Mutation **Key Point:** This patient has a **de novo (new) WT1 mutation** because the father is phenotypically normal and does not carry the mutation. The mutation arose spontaneously in the patient's germline or early somatic cells. ### Two-Hit Hypothesis in Wilms Tumor **High-Yield:** WT1-associated Wilms tumors follow the **two-hit model**: 1. **First hit:** Germline (or early somatic) WT1 mutation present in all cells 2. **Second hit:** Somatic loss of heterozygosity (LOH) — loss of the normal WT1 allele specifically in the renal epithelial cells that give rise to the tumor Biallelic inactivation of WT1 is required for malignant transformation. ### WT1 Function: Gatekeeper Suppressor **Clinical Pearl:** WT1 is a **zinc-finger transcription factor** that: - Regulates **nephrogenic differentiation** — promotes maturation of renal progenitor cells - Controls **apoptosis** — loss of WT1 allows damaged cells to survive - Suppresses cell proliferation in the developing kidney - Acts as a **gatekeeper** (not caretaker) — directly suppresses tumor formation rather than maintaining genome stability **Mnemonic:** **WT1 = Wilms Tumor suppressor 1 — controls kidney development & cell death** ### Clinical Correlates | Feature | WT1-Associated Wilms Tumor | | --- | --- | | **Inheritance** | Autosomal dominant (germline mutation) or de novo | | **Penetrance** | ~90% (high risk of bilateral disease) | | **Associated Syndromes** | WAGR syndrome (Wilms, Aniridia, GU anomalies, Retardation), Denys-Drash syndrome | | **Mechanism** | Gatekeeper suppressor — loss of differentiation & apoptosis control | | **Tumor Type** | Unilateral or bilateral nephroblastoma | **Warning:** Do not confuse WT1 with **Beckwith-Wiedemann syndrome**, which involves **IGF2 (imprinting defect)** and **H19**, not WT1 mutations. BWS presents with macrosomia, hemihypertrophy, and Wilms tumor risk, but the genetic basis is different. [cite:Robbins 10e Ch 7]