Wilms tumor patient-derived xenografts recapitulate the histology and genetic features of high-risk human primary Wilms tumor

Objective: To establish a Wilms tumor patient-derived xenograft (WTPDX) library that recapitulates the genetic and histologic features of primary Wilms tumor (WT). Methods: Forty-five heterotopic WTPDX were established in... [ view full abstract ]

Objective: To establish a Wilms tumor patient-derived xenograft (WTPDX) library that recapitulates the genetic and histologic features of primary Wilms tumor (WT).

Methods: Forty-five heterotopic WTPDX were established in CB17 scid^-/- mice. WTPDX and WT histology were compared. Mutational screening for TP53, WT1, CTNNB1, SIX1, and SIX2 was performed by Sanger sequencing. Copy number analysis at 1q, 1p, 11p13, 11p15, 16q, 17p, and WTX was performed using Multiplex Probe Ligation Probe Amplification (MLPA). Imprinting and loss of heterozygosity (LOH) status at 11p15 were determined by methylation-sensitive MLPA and fluorescence PCR genotyping.    

Results: WTPDX histology was consistent with WT in all 45 cases.  Five of six WTPDX from unfavorable histology WT were found to have TP53 mutation and/or copy loss at 17p. 11p15 LOH was found in 22 (48.9%) cases and 11p15 loss of imprinting found in 17 (37.7%).  WT1 mutations were identified in 6 cases (13.3%). Copy loss at WT1 (11p13) was identified in 5 cases (11.1%) and homozygous deletion of WT1 in 1 case (2.2%). CTNNB1 mutations were found in 6 cases (13.3%). WTX copy loss was found in 16 cases (35.6%). SIX1 Q177R hotspot mutations were found in 3 cases (6.7%) and SIX2 Q177R mutations were found in 2 cases (4.4%).  There were 12 cases with 1q gain (26.7%), 9 cases with 16q LOH (20%) and one case with LOH at both 1p and 16q.   

Conclusion: WTPDX maintain high-risk genetic and histologic features of WT and are a model for preclinical testing of therapies designed for high-risk tumors.