Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562.
OBJECTIVE
Wilms' tumor is a childhood cancer of the kidney with an incidence of approximately 1 in 10,000. Cooccurrence of Wilms' tumor with 2q37 deletion syndrome, an uncommon constitutional chromosome abnormality, has been reported previously in three children. Given these are independently rare clinical entities, we hypothesized that 2q37 harbors a tumor suppressor gene important in Wilms' tumor pathogenesis.


METHODS
To test this, we performed loss of heterozygosity analysis in a panel of 226 sporadic Wilms' tumor samples and mutation analysis of candidate genes.


RESULTS
Loss of heterozygosity was present in at least 4% of cases. Two tumors harbored homozygous deletions at 2q37.1, supporting the presence of a tumor suppressor gene that follows a classic two-hit model. However, no other evidence of second mutations was found, suggesting that heterozygous deletion alone may be sufficient to promote tumorigenesis in concert with other genomic abnormalities. We show that miR-562, a microRNA within the candidate region, is expressed only in kidney and colon and regulates EYA1, a critical gene for renal development. miR-562 expression is reduced in Wilms' tumor and may contribute to tumorigenesis by deregulating EYA1. Two other candidate regions were localized at 2q37.3 and 2qter, but available data from patients with constitutional deletions suggest that these probably do not confer a high risk for Wilms' tumor.


CONCLUSIONS
Our data support the presence of a tumor suppressor gene at 2q37.1 and suggest that, in individuals with constitutional 2q37 deletions, any increased risk for developing Wilms' tumor likely correlates with deletions encompassing 2q37.1.
Drake
Kylie M
KM
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Ruteshouser
E Cristy
EC
Natrajan
Rachael
R
Harbor
Phyllis
P
Wegert
Jenny
J
Gessler
Manfred
M
Pritchard-Jones
Kathy
K
Grundy
Paul
P
Dome
Jeffrey
J
Huff
Vicki
V
Jones
Chris
C
Aldred
Micheala A
MA
D002478:Cells, Cultured; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007680:Kidney Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011110:Polymorphism, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C545728:MIRN562 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C104381:EYA1 protein, human; D017027:Protein Tyrosine Phosphatases