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Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets
European Urology ( IF 25.3 ) Pub Date : 2017-06-03 , DOI: 10.1016/j.eururo.2017.05.032
Eugene J Pietzak 1 , Aditya Bagrodia 1 , Eugene K Cha 1 , Esther N Drill 2 , Gopa Iyer 3 , Sumit Isharwal 1 , Irina Ostrovnaya 2 , Priscilla Baez 1 , Qiang Li 1 , Michael F Berger 4 , Ahmet Zehir 4 , Nikolaus Schultz 5 , Jonathan E Rosenberg 6 , Dean F Bajorin 6 , Guido Dalbagni 1 , Hikmat Al-Ahmadie 4 , David B Solit 3 , Bernard H Bochner 1
Affiliation  

Background

Molecular characterization of nonmuscle invasive bladder cancer (NMIBC) may provide a biologic rationale for treatment response and novel therapeutic strategies.

Objective

To identify genetic alterations with potential clinical implications in NMIBC.

Design, setting, and participants

Pretreatment index tumors and matched germline DNA from 105 patients with NMIBC on a prospective Institutional Review Board-approved protocol underwent targeted exon sequencing analysis in a Clinical Laboratory Improvement Amendments-certified clinical laboratory.

Outcome measurements and statistical analysis

Comutation patterns and copy number alterations were compared across stage and grade. Associations between genomic alterations and recurrence after intravesical bacillus Calmette-Guérin (BCG) were estimated using Kaplan-Meier and Cox regression analyses.

Results and limitations

TERT promoter mutations (73%) and chromatin-modifying gene alterations (69%) were highly prevalent across grade and stage, suggesting these events occur early in tumorigenesis. ERBB2 or FGFR3 alterations were present in 57% of high-grade NMIBC tumors in a mutually exclusive pattern. DNA damage repair (DDR) gene alterations were seen in 30% (25/82) of high-grade NMIBC tumors, a rate similar to MIBC, and were associated with a higher mutational burden compared with tumors with intact DDR genes (p < 0.001). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio = 3.14, 95% confidence interval: 1.51–6.51, p = 0.002).

Conclusions

Next-generation sequencing of treatment-naive index NMIBC tumors demonstrated that the majority of NMIBC tumors had at least one potentially actionable alteration that could serve as a target in rationally designed trials of intravesical or systemic therapy. DDR gene alterations were frequent in high-grade NMIBC and were associated with increased mutational load, which may have therapeutic implications for BCG immunotherapy and ongoing trials of systemic checkpoint inhibitors. ARID1A mutations were associated with an increased risk of recurrence after BCG therapy. Whether ARID1A mutations represent a predictive biomarker of BCG response or are prognostic in NMIBC patients warrants further investigation.

Patient summary

Analysis of frequently mutated genes in superficial bladder cancer suggests potential targets for personalized treatment and predictors of treatment response, and also may help develop noninvasive tumor detection tests.



中文翻译:


非肌肉浸润性膀胱癌的下一代测序揭示了潜在的生物标志物和合理的治疗靶点


 背景


非肌层浸润性膀胱癌(NMIBC)的分子特征可能为治疗反应和新的治疗策略提供生物学原理。

 客观的


鉴定 NMIBC 中具有潜在临床意义的基因改变。


设计、设置和参与者


根据机构审查委员会批准的前瞻性方案,预处理索引肿瘤和来自 105 名 NMIBC 患者的匹配种系 DNA 在临床实验室改进修正案认证的临床实验室中进行了靶向外显子测序分析。


结果测量和统计分析


比较不同阶段和年级的交换模式和拷贝数变化。使用 Kaplan-Meier 和 Cox 回归分析估计基因组改变与膀胱内卡介苗 (BCG) 复发之间的关联。

 结果和局限性


TERT启动子突变 (73%) 和染色质修饰基因改变 (69%) 在各个年级和阶段都非常普遍,表明这些事件发生在肿瘤发生的早期。 57% 的高级别 NMIBC 肿瘤中存在ERBB2FGFR3改变,且呈相互排斥的模式。 DNA 损伤修复 (DDR) 基因改变出现在 30% (25/82) 的高级 NMIBC 肿瘤中,这一比例与 MIBC 相似,并且与具有完整 DDR 基因的肿瘤相比,与更高的突变负担相关 ( p < 0.001 )。 ARID1A突变与 BCG 后复发风险增加相关(风险比 = 3.14,95% 置信区间:1.51–6.51, p = 0.002)。

 结论


对初治指数 NMIBC 肿瘤的下一代测序表明,大多数 NMIBC 肿瘤至少有一种潜在的可行改变,可以作为合理设计的膀胱内或全身治疗试验的目标。 DDR 基因改变在高级别 NMIBC 中很常见,并且与突变负荷增加相关,这可能对 BCG 免疫疗法和正在进行的全身检查点抑制剂试验具有治疗意义。 ARID1A突变与 BCG 治疗后复发风险增加相关。 ARID1A突变是否代表 BCG 反应的预测生物标志物或 NMIBC 患者的预后值得进一步研究。

 患者总结


浅表性膀胱癌中频繁突变基因的分析表明了个性化治疗的潜在目标和治疗反应的预测因子,并且还可能有助于开发非侵入性肿瘤检测测试。

更新日期:2017-06-03
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