WT1 gene

Evidence of WNT pathway activation by activating variants in the CTNNB1 gene is common.[13-15]

Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.[13,16]

Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests occur in approximately 20% of Wilms tumor cases. They are observed at high rates in cases with genetic syndromes that have WT1 variants such as WAGR and Denys-Drash syndromes.[17] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 variants.[18,19]

WT1 germline pathogenic variants are uncommon (2%–4%) in nonsyndromic Wilms tumor.[20,21]

WT1 variants and 11p15 LOH were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[22] These findings need validation but may provide biomarkers for stratifying patients in the future.

WAGR syndrome, Denys-Drash syndrome,[23] or Frasier syndrome.[24]

Genitourinary anomalies, including hypospadias and cryptorchidism.

Bilateral Wilms tumor.

Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.

Stromal and rhabdomyomatous differentiation.

WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[27] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that include the WT1 and PAX6 genes. Inactivating variants or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Loss of the LMO2 gene has been associated with a more frequent development of Wilms tumor in patients with congenital aniridia and WAGR-region deletions.[28][Level of evidence C1] Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[29,30] Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests, early age at diagnosis, and stromal-predominant histology in FH tumors.[31] The intellectual disability in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[32]

Denys-Drash syndrome. This syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%). WT1 variants in Denys-Drash syndrome are most often missense variants in exons 8 and 9, which code for the DNA binding region of WT1.[23]

Frasier syndrome. This syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.WT1 variants in Frasier syndrome typically occur in intron 9 at the KT site, and create an alternative splicing variant, thereby preventing production of the usually more abundant WT1 +KTS isoform.[33]