Drake Kylie M, Ruteshouser E Cristy, Natrajan Rachael, Harbor Phyllis, Wegert Jenny, Gessler Manfred, Pritchard-Jones Kathy, Grundy Paul, Dome Jeffrey, Huff Vicki, Jones Chris, Aldred Micheala A
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Clin Cancer Res. 2009 Oct 1;15(19):5985-92. doi: 10.1158/1078-0432.CCR-09-1065. Epub 2009 Sep 29.
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.
To test this, we performed loss of heterozygosity analysis in a panel of 226 sporadic Wilms' tumor samples and mutation analysis of candidate genes.
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.
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.
肾母细胞瘤是一种儿童期肾癌，发病率约为万分之一。此前曾有报道称，三名儿童同时患有肾母细胞瘤和2q37缺失综合征，后者是一种罕见的染色体结构异常。鉴于这两种疾病本身都很罕见，我们推测2q37区域存在一个对肾母细胞瘤发病机制至关重要的肿瘤抑制基因。
为验证这一推测，我们对226例散发性肾母细胞瘤样本进行了杂合性缺失分析，并对候选基因进行了突变分析。
至少4%的病例存在杂合性缺失。有两个肿瘤在2q37.1区域发生了纯合缺失，支持了存在一个遵循经典双打击模型的肿瘤抑制基因的观点。然而，未发现其他二次突变的证据，这表明单独的杂合性缺失可能与其他基因组异常协同作用，足以促进肿瘤发生。我们发现，候选区域内的一种 microRNA（miR-562）仅在肾脏和结肠中表达，并调控EYA1（肾脏发育的关键基因）。肾母细胞瘤中miR-562的表达降低，可能通过失调EYA1促进肿瘤发生。另外两个候选区域定位于2q37.3和2qter，但来自染色体结构缺失患者的现有数据表明，这些区域可能不会显著增加肾母细胞瘤的发病风险。
我们的数据支持2q37.1区域存在肿瘤抑制基因，并表明在染色体2q37结构缺失的个体中，发生肾母细胞瘤风险的增加可能与包含2q37.1的缺失有关。
