Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562.
Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR-562.
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DOI：
10.1158/1078-0432.ccr-09-1065
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发表时间：
2009-10-01
期刊：
影响因子：
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通讯作者：
Aldred MA
中科院分区：
文献类型：
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作者：
Drake KM;Ruteshouser EC;Natrajan R;Harbor P;Wegert J;Gessler M;Pritchard-Jones K;Grundy P;Dome J;Huff V;Jones C;Aldred MA
肾母细胞瘤是一种儿童期肾癌，发病率约为万分之一。Wilms肿瘤与2q37缺失综合征（一种罕见的体质染色体异常）的共同发生在三个儿童中。鉴于这些是独立罕见的临床实体，我们假设2q37含有在Wilms肿瘤发病机制中重要的肿瘤抑制基因。为了验证这一点，我们对226例散发性Wilms肿瘤样本进行了杂合性缺失（LOH）分析，并对候选基因进行了突变分析。至少4%的病例存在LOH。两个肿瘤在2q37.1处存在纯合缺失，支持肿瘤抑制基因的存在，遵循经典的双重打击模型。然而，没有发现第二突变的其他证据，这表明杂合缺失可能足以促进肿瘤发生，并伴有其他基因组异常。我们发现候选区域内的microRNA miR-562仅在肾脏和结肠中表达，并调节肾脏发育的关键基因EYA1。miR-562在Wilms肿瘤中的表达降低，并可能通过调节EYA1而促进肿瘤发生。另外两个候选区域定位于2q37.3和2q2 . 4，但来自体质缺失患者的现有数据表明，这些可能不会导致Wilms肿瘤的高风险。我们的数据支持在2q37.1处存在肿瘤抑制基因，并提示在体质缺失2q37的个体中，任何发生Wilms肿瘤的风险增加可能与缺失2q37.1有关。
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. 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. 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. 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.