Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada.
Department of Cellular Pathology, University Hospital of Wales/Cardiff University School of Medicine, Cardiff, UK.
Mod Pathol. 2018 Jan;31(1):169-178. doi: 10.1038/modpathol.2017.100. Epub 2017 Sep 1.
Anaplastic sarcoma of the kidney is a rare tumor (≤25 reported cases) characterized by the presence of cysts, and solid areas composed of bundles of undifferentiated spindle cells, showing marked cellular anaplasia (usually accompanied by TP53 overexpression). These tumors often feature prominent areas of cartilage or chondroid material. Germline mutations in DICER1, encoding the microRNA (miRNA) processor DICER1, cause an eponymous syndrome. Recent reports suggest that anaplastic sarcoma of the kidney should be included in DICER1 syndrome as germline DICER1 mutations are associated with the occurrence of such tumors. Therefore, we sought to determine the following: (1) what proportion of anaplastic sarcoma of the kidney have DICER1 mutations; (2) whether the identified mutations affect both alleles of DICER1 (ie, are biallelic); (3) whether somatic missense mutations in the DICER1 RNase IIIb domain impact miRNA generation; and (4) whether TP53 alteration always occurs in these tumors. DICER1 mutations were evaluated by Sanger sequencing and next-generation sequencing in nine tumor/normal pairs. Impact of DICER1 mutations on miRNA generation was evaluated via an in vitro DICER1 cleavage assay. TP53 status was assessed by immunohistochemistry and next-generation sequencing. Eight of the nine cases had at least one RNase IIIb DICER1 mutation that impacted the generation of miRNAs. There were six tumors with truncating DICER1 mutations and in four of them, the mutation found in the tumor was also detected in adjacent normal tissue, and therefore was likely to be either mosaic or germline in origin. Analysis of mutation phase revealed that two of three tumors had biallelic DICER1 mutations. Six of nine anaplastic sarcomas of the kidney had aberrant TP53 immunohistochemisty with damaging TP53 mutations identified in three cases. Taken together, these data suggest that the great majority of anaplastic sarcomas of the kidney have DICER1 mutations and confirm that these tumors are part of the DICER1 syndrome.
肾嫌色细胞肉瘤是一种罕见的肿瘤（<25 例报告），其特征为存在囊肿和由未分化梭形细胞束组成的实性区域，表现出明显的细胞异型性（通常伴有 TP53 过表达）。这些肿瘤常具有明显的软骨或软骨样物质区域。DICER1 基因（编码 miRNA 加工酶 DICER1）的种系突变导致一种同名综合征。最近的报道表明，肾嫌色细胞肉瘤应包含在 DICER1 综合征中，因为种系 DICER1 突变与这些肿瘤的发生有关。因此，我们试图确定以下几点：（1）有多少比例的肾嫌色细胞肉瘤存在 DICER1 突变；（2）所鉴定的突变是否影响 DICER1 的两个等位基因（即是否为双等位基因）；（3）DICER1 RNase IIIb 结构域中的体细胞错义突变是否影响 miRNA 的生成；以及（4）这些肿瘤中是否总是存在 TP53 改变。通过 Sanger 测序和下一代测序对 9 对肿瘤/正常组织进行了 DICER1 突变检测。通过体外 DICER1 切割实验评估 DICER1 突变对 miRNA 生成的影响。通过免疫组化和下一代测序评估 TP53 状态。9 例中有 8 例至少存在一个影响 miRNA 生成的 RNase IIIb DICER1 突变。有 6 例肿瘤存在截断 DICER1 突变，其中 4 例肿瘤中发现的突变也在相邻正常组织中检测到，因此可能是镶嵌性或种系来源。突变相位分析显示，有 2/3 的肿瘤存在双等位基因 DICER1 突变。在 9 例肾嫌色细胞肉瘤中有 6 例存在异常的 TP53 免疫组化，其中 3 例存在有损伤的 TP53 突变。综上所述，这些数据表明，绝大多数肾嫌色细胞肉瘤存在 DICER1 突变，并证实这些肿瘤是 DICER1 综合征的一部分。
