Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

Abstract

Purpose Wilms tumor is a childhood cancer of the kidney with an incidence of ~1 in 10,000. Co-occurrence of Wilms tumor with 2q37 deletion syndrome, an uncommon constitutional chromosome abnormality, has previously been reported in three children. Given these are independently rare clinical entities, we hypothesized that 2q37 harbors a tumor suppressor gene important in Wilms tumor pathogenesis. Experimental Design To test this, we performed loss of heterozygosity (LOH) analysis in a panel of 226 sporadic Wilms tumor samples and mutation analysis of candidate genes. Results LOH 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 classical 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 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.

The yin and yang of kidney development and Wilms’ tumors

“…Similar findings in several other studies showed that down-regulation of miR-562, miR-204, and miR-185 correlated with increased expression of EYA1 (Drake et al 2009), MEIS1, and SIX1 (Imam et al 2010), respectively. In particular, miR-185 was shown to inhibit anchorage-independent growth and cell migration in addition to suppressing tumor growth in vivo, implicating it as a potent tumor suppressor silenced in Wilms' tumor (Imam et al 2010).…”

Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

“…In the other case, WT227, the deletion was much smaller, encompassing approximately 50 kb (chr2: 232,699,749,125), and involved the DIS3L2 and miR-562 genes only. To the best of our knowledge, this is the smallest homozygous deletion involving miR-562 reported to date in a WT (Drake et al, 2009). This finding provides further support to the hypothesis that the loss of this microRNA, which regulates EYA1, a critical gene for renal development, may contribute to WT development.…”

Wilms tumor incidence in children with 2q terminal deletions: A cohort study

“…Recently, loss of heterozygosity at 2q37 has been shown in 4% of sporadic Wilms tumors [Drake et al, 2009]. miR-562 expression was reduced in Wilms tumor and it has been suggested that this is a putative tumor suppressor gene at 2q37.1.…”

“…A 2q36.3-2q37.1 microdeletion was reported in 8 out of a series of 37 relapsing Wilms tumors [Natrajan et al, 2006]. Furthermore, a recent study has also demonstrated loss of heterozygosity at 2q37 in sporadic Wilms tumor, and suggested a putative role for miR-562 as a tumor suppressor [Drake et al, 2009].…”