Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
J Exp Clin Cancer Res. 2010 Nov 16;29(1):147. doi: 10.1186/1756-9966-29-147.
Deletions within the short arm of chromosome 7 are observed in approximately 25% of adult and 10% of Wilms pediatric renal tumors. Within Wilms tumors, the region of interest has been delineated to a 2-Mb minimal region that includes ten known genes. Two of these ten candidate genes, SOSTDC1 and MEOX2, are particularly relevant to tumor development and maintenance. This finding, coupled with evidence that SOSTDC1 is frequently downregulated in adult renal cancer and regulates both Wingless-Int (Wnt)- and bone morphogenetic protein (BMP)-induced signaling, points to a role for SOSTDC1 as a potential tumor suppressor.
To investigate this hypothesis, we interrogated the Oncomine database to examine the SOSTDC1 levels in adult renal clear cell tumors and pediatric Wilms tumors. We then performed single nucleotide polymorphism (SNP) and sequencing analyses of SOSTDC1 in 25 pediatric and 36 adult renal tumors. Immunohistochemical staining of patient samples was utilized to examine the impact of SOSTDC1 genetic aberrations on SOSTDC1 protein levels and signaling.
Within the Oncomine database, we found that SOSTDC1 levels were reduced in adult renal clear cell tumors and pediatric Wilms tumors. Through SNP and sequencing analyses of 25 Wilms tumors, we identified four with loss of heterozygosity (LOH) at 7p and three that affected SOSTDC1. Of 36 adult renal cancers, we found five with LOH at 7p, two of which affected SOSTDC1. Immunohistochemical analysis of SOSTDC1 protein levels within these tumors did not reveal a relationship between these instances of SOSTDC1 LOH and SOSTDC1 protein levels. Moreover, we could not discern any impact of these genetic alterations on Wnt signaling as measured by altered beta-catenin levels or localization.
This study shows that genetic aberrations near SOSTDC1 are not uncommon in renal cancer, and occur in adult as well as pediatric renal tumors. These observations of SOSTDC1 LOH, however, did not correspond with changes in SOSTDC1 protein levels or signaling regulation. Although our conclusions are limited by sample size, we suggest that an alternative mechanism such as epigenetic silencing of SOSTDC1 may be a key contributor to the reduced SOSTDC1 mRNA and protein levels observed in renal cancer.
在大约 25%的成人和 10%的小儿肾母细胞瘤中观察到 7 号染色体短臂缺失。在肾母细胞瘤中，已将感兴趣的区域划定为包括十个已知基因的 2-Mb 最小区域。这十个候选基因中的两个，SOSTDC1 和 MEOX2，与肿瘤的发生和维持特别相关。这一发现，加上 SOSTDC1 在成人肾癌中经常下调的证据，并调节 Wingless-Int（Wnt）和骨形态发生蛋白（BMP）诱导的信号，表明 SOSTDC1 作为潜在的肿瘤抑制基因发挥作用。
为了研究这一假说，我们在 Oncomine 数据库中调查了成人肾透明细胞肿瘤和小儿肾母细胞瘤中 SOSTDC1 的水平。然后，我们对 25 例小儿和 36 例成人肾肿瘤进行了 SOSTDC1 的单核苷酸多态性（SNP）和测序分析。利用患者样本的免疫组织化学染色来检查 SOSTDC1 遗传异常对 SOSTDC1 蛋白水平和信号的影响。
在 Oncomine 数据库中，我们发现 SOSTDC1 水平在成人肾透明细胞肿瘤和小儿肾母细胞瘤中降低。通过对 25 例 Wilms 肿瘤的 SNP 和测序分析，我们发现其中 4 例存在 7p 杂合性丢失（LOH），3 例影响 SOSTDC1。在 36 例成人肾癌中，我们发现 5 例存在 7p LOH，其中 2 例影响 SOSTDC1。对这些肿瘤中 SOSTDC1 蛋白水平的免疫组织化学分析并未显示出 SOSTDC1 LOH 与 SOSTDC1 蛋白水平之间存在任何关系。此外，我们无法发现这些遗传改变对 Wnt 信号的任何影响，如通过改变 beta-catenin 水平或定位来衡量。
本研究表明，SOSTDC1 附近的遗传异常在肾癌中并不少见，并且发生在成人和小儿肾肿瘤中。然而，这些 SOSTDC1 LOH 的观察结果与 SOSTDC1 蛋白水平或信号调节的变化并不对应。尽管我们的结论受到样本量的限制，但我们认为，SOSTDC1 的表观遗传沉默等替代机制可能是导致肾癌中观察到的 SOSTDC1 mRNA 和蛋白水平降低的关键因素。
