British Columbia Cancer Research Centre, Vancouver, BC, Canada.
N Engl J Med. 2012 Jan 19;366(3):234-42. doi: 10.1056/NEJMoa1102903. Epub 2011 Dec 21.
Germline truncating mutations in DICER1, an endoribonuclease in the RNase III family that is essential for processing microRNAs, have been observed in families with the pleuropulmonary blastoma-family tumor and dysplasia syndrome. Mutation carriers are at risk for nonepithelial ovarian tumors, notably sex cord-stromal tumors.
We sequenced the whole transcriptomes or exomes of 14 nonepithelial ovarian tumors and noted closely clustered mutations in the region of DICER1 encoding the RNase IIIb domain of DICER1 in four samples. We then sequenced this region of DICER1 in additional ovarian tumors and in certain other tumors and queried the effect of the mutations on the enzymatic activity of DICER1 using in vitro RNA cleavage assays.
DICER1 mutations in the RNase IIIb domain were found in 30 of 102 nonepithelial ovarian tumors (29%), predominantly in Sertoli-Leydig cell tumors (26 of 43, or 60%), including 4 tumors with additional germline DICER1 mutations. These mutations were restricted to codons encoding metal-binding sites within the RNase IIIb catalytic centers, which are critical for microRNA interaction and cleavage, and were somatic in all 16 samples in which germline DNA was available for testing. We also detected mutations in 1 of 14 nonseminomatous testicular germ-cell tumors, in 2 of 5 embryonal rhabdomyosarcomas, and in 1 of 266 epithelial ovarian and endometrial carcinomas. The mutant DICER1 proteins had reduced RNase IIIb activity but retained RNase IIIa activity.
Somatic missense mutations affecting the RNase IIIb domain of DICER1 are common in nonepithelial ovarian tumors. These mutations do not obliterate DICER1 function but alter it in specific cell types, a novel mechanism through which perturbation of microRNA processing may be oncogenic. (Funded by the Terry Fox Research Institute and others.).
DICER1 是 RNase III 家族的一种内切核酸酶，对于 microRNA 的加工至关重要。胚肺母细胞瘤-肿瘤和发育不良综合征家族中已观察到 DICER1 胚系截短突变。突变携带者存在发生非上皮性卵巢肿瘤的风险，特别是性索-间质肿瘤。
我们对 14 例非上皮性卵巢肿瘤进行了全转录组或外显子组测序，并在 4 个样本中注意到 DICER1 的 RNase IIIb 结构域编码区域中紧密聚集的突变。然后，我们在其他卵巢肿瘤和某些其他肿瘤中测序了 DICER1 的这个区域，并使用体外 RNA 切割测定法查询突变对 DICER1 酶活性的影响。
在 102 例非上皮性卵巢肿瘤中发现 DICER1 的 RNase IIIb 结构域突变 30 例（29%），主要见于 Sertoli-Leydig 细胞肿瘤（43 例中的 26 例，即 60%），包括 4 例肿瘤伴有额外的胚系 DICER1 突变。这些突变仅限于编码 RNase IIIb 催化中心金属结合位点的密码子，这些突变对于 microRNA 的相互作用和切割至关重要，并且在所有 16 个可供测试的样本中均为体细胞突变。我们还在 14 例非精原细胞瘤性睾丸生殖细胞肿瘤、5 例胚胎性横纹肌肉瘤和 266 例上皮性卵巢和子宫内膜癌中的 1 例中检测到突变。突变的 DICER1 蛋白的 RNase IIIb 活性降低，但保留 RNase IIIa 活性。
影响 DICER1 RNase IIIb 结构域的体细胞错义突变在非上皮性卵巢肿瘤中很常见。这些突变没有破坏 DICER1 功能，但在特定细胞类型中改变了其功能，这是一种通过扰乱 microRNA 加工而致癌的新机制。（由 Terry Fox 研究所以及其他机构资助）。
