The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes

Approximately 5% of patients with Wilms tumor present with synchronous bilateral disease. The development of synchronous bilateral Wilms tumor (BWT) is highly suggestive of a genetic or epigenetic predisposition. Patients with known germline predisposition to Wilms tumor (WT1 variants, Beckwith Wiedemann spectrum, TRIM28 variants) have a higher incidence of BWT. This Children's Oncology Group (COG)-International Society for Pediatric Oncology (SIOP-) HARMONICA initiative review for pediatric renal tumors details germline genetic and epigenetic predisposition to BWT development, with an emphasis on alterations in 11p15.5 (ICR1 gain of methylation, paternal uniparental disomy, and postzygotic somatic mosaicism), WT1, TRIM28, and REST. Molecular mechanisms that result in BWT are often also present in multifocal Wilms tumor (multiple separate tumors in one or both kidneys). We identify priority areas for international collaborative research to better understand how predisposing genetic or epigenetic factors associate with response to neoadjuvant chemotherapy, oncologic outcomes, and long-term renal function outcomes.

Automated summary

Approximately 5% of Wilms tumor patients have synchronous bilateral disease, indicating a genetic or epigenetic predisposition. This review article focuses on the genetic and epigenetic factors related to the development of synchronous bilateral Wilms tumor, with emphasis on alterations in 11p15.5 and specific genes like WT1, TRIM28, and REST. The article also identifies priority areas for international collaborative research to better understand the relationship between genetic or epigenetic factors and chemotherapy response, oncologic outcomes, and long-term renal function.