Journal of Clinical Oncology, Vol 16, 3634-3640, Copyright © 1998 by American Society of Clinical Oncology
Constitutional WT1 mutations in Wilms' tumor patients
L Diller, M Ghahremani, J Morgan, P Grundy, C Reeves, N Breslow, D Green, D Neuberg, J Pelletier and FP Li
Dana-Farber Cancer Institute, Boston, MA 02115, USA. lisa_diller@dfci.harvard.edu
PURPOSE: Patients with Wilms' tumors (WT) who carry constitutional
mutations in the WT1 gene have been described in case reports and small
case series. We sought to determine the frequency of constitutional WT1
mutations in a larger cohort, and to identify clinical manifestations
associated with the risk for carrying a WT1 mutation. METHODS: We collected
clinical data and blood samples from 201 patients with a history of WT.
Southern blot analysis, single-strand conformation polymorphism (SSCP)
analysis, and direct DNA sequencing were performed on DNA isolated from
peripheral-blood lymphocytes from each patient. Odds ratios (ORs) for the
carriage of a germline mutation of the WT1 gene were calculated for
patients who had specific clinical risk factors compared with those who did
not. RESULTS: Of 201 patients with WT in the cohort, eight patients were
carriers of mutations in the WT1 gene. Six of the eight mutations were
protein-truncating nonsense mutations. None of 56 patients with isolated
unilateral WT was a carrier. The OR of carrying a WT1 mutation was elevated
for patients with genitourinary anomalies (OR19.3; P < .002). Seven of
28 boys with WT with cryptorchidism carried WT1 mutations. No increased
risk was observed for patients with nephrogenic rests, bilateral tumors,
history of secondary cancers, or family history of WT. CONCLUSION: Germline
WT1 mutations in patients with WT are associated with genitourinary
anomalies, especially cryptorchidism and/or hypospadias. Patients with WT
and no genitourinary anomalies are at low risk for carrying a WT1 mutation.
Constitutional WT1 mutations that encode truncated WT1 proteins may
predispose to the development of cryptorchidism, hypospadias, and WTs.
