Molecular Characterization of Metanephric Adenoma, Epithelial Wilms Tumor, and Overlap Lesions: An Integrated Whole-exome and Transcriptome Sequencing Analysis
Molecular Characterization of Metanephric Adenoma, Epithelial Wilms Tumor, and Overlap Lesions: An Integrated Whole-exome and Transcriptome Sequencing Analysis
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DOI：
10.1097/pai.0000000000000996
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发表时间：
2022-04-01
影响因子：
1.6
通讯作者：
Epstein, Jonathan, I
中科院分区：
文献类型：
--
作者：
Pan, Chin-Chen;Tseng, Chih-En;Epstein, Jonathan, I
后肾腺瘤（MA）和肾母细胞瘤（WT）代表了两种与胚胎肾小管非常相似的原发性肾脏肿瘤的原型。可能会发生具有重叠特征的肿瘤，需要在2之间进行鉴别诊断。已经报道了不同致癌途径的证据，表明MA是由BRAF突变驱动的，而大多数WT是BRAF野生型。我们收集了4例MA病例，3例同相上皮WT病例，1例重叠后肾肿瘤，该肿瘤包含常规MA和类似于上皮WT的高级别成分。进行全外显子组测序和全转录组测序以发现突变、体细胞拷贝数变异和差异表达。将结果与TARGET数据库（WT-TARGET）的WT结果进行比较。BRAF V600 E突变在所有MA以及重叠肿瘤中检测到，但在所有上皮WT和WT-靶中检测不到。重叠肿瘤显示了SETD 2的额外致病突变。在WT-TARGET中观察到的三种常见基因突变在上皮WT中并不常见，其中突变出现散发。复发性拷贝数变异的概况在MA、上皮WT和WT-靶之间都不同。差异表达和无监督的层次聚类分析揭示了3类不同的集群。值得注意的是，重叠肿瘤与MA共聚集，与上皮WT和WT-靶分离。MA和WT的独特性从分子角度被证明对应于BRAF突变的和非BRAF突变的途径。BRAF测定对重叠肿瘤具有诊断意义。
Metanephric adenoma (MA) and Wilms tumor (WT) represent 2 prototypes of primary renal neoplasms closely resembling embryonal renal tubules. Tumors with overlapping features may occur, requiring differential diagnoses between the 2. Evidence of divergent oncogenic pathways has been reported, suggesting that MA is driven by BRAF mutation while most WT is of the BRAF wild-type. We collected 4 MA cases, 3 cases of monophasic epithelial WT, and 1 overlap metanephric tumor that contains both conventional MA and high-grade components similar to epithelial WT. Whole-exome sequencing and whole transcriptome sequencing were performed to discover mutations, somatic copy number variation, and differential expression. The findings were compared with those of WT of the TARGET database (WT-TARGET). BRAF V600E mutation was detected in all MAs as well as the overlap tumor but was undetectable in all epithelial WTs and WT-TARGET. The overlap tumor showed an additional pathogenic mutation of SETD2. Three frequent gene mutations observed in WT-TARGET were not common in epithelial WT, in which the mutations appeared sporadic. The profiles of recurrent copy number variations were all different among MA, epithelial WT, and WT-TARGET. Differential expression and unsupervised hierarchical cluster analyses revealed distinct clusters of the 3 categories. Remarkably, the overlap tumor coclustered with MA, separated from epithelial WT and WT-TARGET. The distinctiveness of MA and WT were demonstrated corresponding to BRAF-mutated and non-BRAF-mutated pathways from the molecular perspective. BRAF assay has diagnostic implication for overlap tumors.