Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA.
Department of Pathology, Johns Hopkins University, Baltimore, MD 21287, USA; Department of Pathology, Isfahan University of Medical Sciences, Isfahan Kidney Diseases Research Center, Isfahan 81746 73461, Iran.
Hum Pathol. 2019 Mar;85:1-9. doi: 10.1016/j.humpath.2018.10.033. Epub 2018 Nov 14.
Activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene are the most common genetic alterations in urothelial carcinoma (UC) of the bladder and upper urinary tract. Although the cadherin 1 (CDH1) gene is commonly mutated in the clinically aggressive plasmacytoid variant of urothelial carcinoma (PUC), little is known about their TERT promoter mutation status. A retrospective search of our archives for PUC and UC with plasmacytoid and/or signet ring cell features (2007-2014) was performed. Ten specimens from 10 patients had archived material available for DNA analysis and were included in the study. Intratumoral areas of nonplasmacytoid histology were also evaluated when present. Samples were analyzed for TERT promoter mutations with Safe-SeqS, a sequencing error-reduction technology, and sequenced using a targeted panel of the 10 most commonly mutated genes in bladder cancer on the Illumina MiSeq platform. TERT promoter mutations were detected in specimens with pure and focal plasmacytoid features (6/10). Similar to conventional UC, the predominant mutation identified was g.1295228C>T. In heterogeneous tumors with focal variant histology, concordant mutations were found in plasmacytoid and corresponding conventional, glandular, or sarcomatoid areas. Co-occurring mutations in tumor protein p53 (TP53, 2 cases) and kirsten rat sarcoma (KRAS) viral proto-oncogene (1 case) were also detected. TERT promoter mutations are frequently present in PUC, which provides further evidence that TERT promoter mutations are common events in bladder cancer, regardless of histologic subtype, and supports their inclusion in any liquid biopsy assay for bladder cancer.
在膀胱和上尿路尿路上皮癌（UC）中，端粒酶逆转录酶（TERT）基因启动子的激活突变是最常见的遗传改变。虽然钙黏蛋白 1（CDH1）基因在临床上侵袭性的浆母细胞变异型尿路上皮癌（PUC）中经常发生突变，但对其 TERT 启动子突变状态知之甚少。我们对 2007-2014 年具有浆母细胞和/或印戒细胞特征的 PUC 和 UC 的档案进行了回顾性搜索。10 名患者的 10 个标本有可供 DNA 分析的存档材料，并纳入研究。当存在时，还评估了非浆母细胞组织学的肿瘤内区域。使用 Safe-SeqS 分析标本的 TERT 启动子突变，这是一种测序错误减少技术，并在 Illumina MiSeq 平台上使用膀胱癌中最常见的 10 个基因突变的靶向面板进行测序。在具有纯和局灶性浆母细胞特征的标本中检测到 TERT 启动子突变（6/10）。与传统 UC 相似，鉴定出的主要突变是 g.1295228C>T。在具有局灶性变异组织学的异质性肿瘤中，在浆母细胞和相应的常规、腺体或肉瘤样区域中发现了一致的突变。还检测到肿瘤蛋白 p53（TP53，2 例）和 Kirsten 大鼠肉瘤（KRAS）病毒原癌基因（1 例）的共发生突变。TERT 启动子突变在 PUC 中经常出现，这进一步证明 TERT 启动子突变是膀胱癌的常见事件，无论组织学亚型如何，并支持将其纳入任何膀胱癌液体活检检测。
