Revisiting the Threshold for Cancer Genetics Referral in Patients With Wilms Tumor

Abstract

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in the Journal of Clinical Oncology , to patients seen in their own clinical practice.

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

“…13,19,33,34 The incidence of WT1 pathogenic variants determined by molecular diagnostics is strikingly higher than the incidence of WT1-related Wilms tumor determined by traditional clinical assessment (e.g., ∼1% of WT patients over four National Wilms Tumor Studies were determined to have WAGR or DDS). 34,35 The highest risk of WT is with truncating WT1 variants (78-100%), followed by pathogenic missense variants (29-54%); the risk is comparatively low with intron nine variants (0-5%). [30][31][32] WT risk in patients with WAGR ranges from 45 to 60%.…”

“…45,50 A comprehensive review of each of these genes and the association with Wilms tumor has recently been published. 34 This genetic heterogeneity translates into a wide range of biological processes. Additional WT predisposition genes are suspected to exist as many syndromic cases do not carry a pathogenic variant in one of the known WT predisposition genes.…”

“…Constitutional WT1 heterozygous pathogenic variants are present in 8–11% of all patients with WT and in approximately 2–7% of patients without syndromic features 13,19,33,34 . The incidence of WT1 pathogenic variants determined by molecular diagnostics is strikingly higher than the incidence of WT1 ‐related Wilms tumor determined by traditional clinical assessment (e.g., ∼1% of WT patients over four National Wilms Tumor Studies were determined to have WAGR or DDS) 34,35 . The highest risk of WT is with truncating WT1 variants (78–100%), followed by pathogenic missense variants (29–54%); the risk is comparatively low with intron nine variants (0–5%) 30–32 .…”

“…To date, more than 21 WT predisposition genes have been identified 45,50 . A comprehensive review of each of these genes and the association with Wilms tumor has recently been published 34 . This genetic heterogeneity translates into a wide range of biological processes.…”

Genetic predisposition to cancers in children and adolescents

“…Wilms tumours are closely linked to a wide array of genetic and epigenetic conditions, including rare constitutional chromosome abnormality disorders that are associated with congenital anomalies, and growth and intellectual developmental impairment [57,58]. Congenital anomalies are observed in approximately 8% of Wilms tumours patients, which is the highest percentage among major paediatric cancers [59].…”