Next-Generation Sequencing Reveals Potential Predictive Biomarkers and Targets of Therapy for Urothelial Carcinoma in Situ of the Urinary Bladder
Next-Generation Sequencing Reveals Potential Predictive Biomarkers and Targets of Therapy for Urothelial Carcinoma in Situ of the Urinary Bladder
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DOI：
10.1016/j.ajpath.2019.10.004
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发表时间：
2020-02-01
影响因子：
6
通讯作者：
Knuechel, Ruth
中科院分区：
文献类型：
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作者：
Garczyk, Stefan;Ortiz-Bruechle, Nadina;Knuechel, Ruth
肿瘤切除后的卡介苗灌注是尿路上皮原位癌（CIS）的一线治疗，CIS是大多数肌肉浸润性膀胱癌的前驱病变。卡介苗治疗在>50%的病例中失败，二线根治性化疗与过度治疗和严重的生活方式后果有关。考虑到对替代性膀胱保留疗法的需求，我们确定了尿路上皮CIS中的基因组改变（GA），其具有预测靶向治疗反应的潜力。应用激光捕获显微切割技术从26例新鲜冷冻的膀胱标本中分离出30例标本（25例CIS和5例肌肉对照）。进行了31个基因的靶向下一代测序。该小组包括在非乳头状起源的肌肉浸润性膀胱癌中经常受影响的基因，重点是描述为预测对已批准的靶向治疗或注册临床试验中的药物的反应的潜在可操作的GA。在CIS患者中，92%的患者携带至少一种潜在的可采取行动的GA，其在TP 53/细胞周期途径相关基因中被鉴定（例如，TP 53和MDM 2）在72%，编码染色质修饰蛋白的基因（例如，ARID 1A和KDM 6A），DNA损伤修复基因，在60%的病例中检测到BRCA 2和ATM基因，在36%的病例中检测到磷脂酰肌醇3激酶/丝裂原活化蛋白激酶途径基因（例如ERBB 2和FGFR 1）。这些数据可能有助于指导未来CIS临床试验中靶向治疗的选择，并为未来尿路上皮CIS发病机制的研究提供基础。
Bacillus Calmette-Guerin instillation after removal of the tumor is the first line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guerin therapy fails in >50% of cases, and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies. Laser-capture microdissection was applied to isolate 30 samples (25 CIS and 5 muscle controls) from 26 fresh-frozen cystectomy specimens. Targeted next-generation sequencing of 31 genes was performed. The panel comprised genes frequently affected in muscle invasive bladder cancer of nonpapillary origin, focusing on potentially actionable GAs described to predict response to approved targeted therapies or drugs that are in registered clinical trials. Of CIS patients, 92% harbored at least one potentially actionable GA, which was identified in TP53/cell cycle pathway related genes (eg, TP53 and MDM2) in 72%, genes encoding chromatin-modifying proteins (eg, ARID1A and KDM6A) in 68%, DNA damage repair genes (eg, BRCA2 and ATM) in 60%, and phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes (eg, ERBB2 and FGFR1) in 36% of the cases. These data might help guide the selection of targeted therapies to be investigated in future clinical CIS trials, and they may provide a basis for future mechanistic studies of urothelial CIS pathogenesis.