Loss of imprinting of insulin-like growth factor-II (IGF2) gene in distinguishing specific biologic subtypes of Wilms tumor.
BACKGROUND
Loss of imprinting (LOI) of the insulin-like growth factor-II (IGF2) gene, an epigenetic alteration associated with expression of the normally silent maternal allele, was observed first in Wilms tumor. Although LOI has subsequently been detected in most adult tumors, the biologic role of LOI in cancer remains obscure. We analyzed the imprinting status of Wilms tumors with respect to pathologic subtype, stage, and patient's age at diagnosis and examined the expression of genes potentially affected by LOI.


METHODS
Of 60 Wilms tumors examined, 25 were informative for an ApaI polymorphism in the IGF2 gene, allowing analysis of allele-specific gene expression, and could be classified by pathologic subtype. Gene expression was measured quantitatively by real-time polymerase chain reaction, and pathologic analysis was blinded for genetic status. All statistical tests were two-sided.


RESULTS
We observed LOI of IGF2 in nine (90%) of 10 Wilms tumors classified as having a pathologic subtype associated with a later stage of renal development and in only one (6.7%) of 15 Wilms tumors with a pathologic subtype associated with an earlier stage of renal development (P< .001). LOI was associated with a 2.2-fold increase (95% confidence interval [CI] = 1.6-fold to 3.1-fold) in IGF2 expression (P< .001). Children whose Wilms tumors displayed LOI of IGF2 were statistically significantly older at diagnosis (median = 65 months; interquartile range [IQR] = 47-83 months) than children whose tumors displayed normal imprinting (median = 24 months; IQR = 13-35 months; P< .001).


CONCLUSIONS
These data demonstrate a clear relationship between LOI and altered expression of IGF2 in Wilms tumors and provide a molecular basis for understanding the divergent pathogenesis of this cancer. Analysis of LOI could provide a valuable molecular tool for the classification of Wilms tumor.
Ravenel
J D
JD
Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Broman
K W
KW
Perlman
E J
EJ
Niemitz
E L
EL
Jayawardena
T M
TM
Bell
D W
DW
Haber
D A
DA
Uejima
H
H
Feinberg
A P
AP
D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D016162:Genes, Wilms Tumor; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D007223:Infant; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D019656:Loss of Heterozygosity / Q000235:genetics; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D009396:Wilms Tumor / Q000145:classification* / Q000235:genetics* / Q000473:pathology
D007335:Insulin-Like Growth Factor II