Frequency and Nature of Genomic Alterations in ERBB2-Altered Urothelial Bladder Cancer

IF 4.4 3区医学 Q2 ONCOLOGY

Targeted Oncology Pub Date : 2024-04-03 DOI:10.1007/s11523-024-01056-x

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引用次数: 0

Abstract

Background

Human epidermal growth factor-2 (HER2) overexpression is an oncogenic driver in many solid tumors, including urothelial bladder cancer (UBC). In addition, activating mutations in the ERBB2 gene have been shown to play an oncogenic role similar to ERBB2 amplification.

Objective

To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.

Patients and Methods

Using a hybrid capture-based comprehensive profiling assay, 9518 UBC cases were grouped by ERBB2 alteration and evaluated for all classes of genomic alterations (GA), tumor mutational burden (TMB), microsatellite instability (MSI), genome-wide loss of heterozygosity (gLOH), and genomic mutational signature. PD-L1 expression was measured by immunohistochemistry (Dako 22C3). Categorical statistical comparisons were performed using Fisher’s exact tests.

Results

A total of 602 (6.3%) UBC cases featured ERBB2 extracellular domain short variant (SV) GA (ECDmut+), 253 (2.7%) cases featured ERBB2 kinase domain SV GA (KDmut+), 866 (9.1%) cases had ERBB2 amplification (amp+), and 7797 (81.9%) cases were ERBB2 wild-type (wt). European genetic ancestry of ECDmut+ was higher than ERBB2wt. Numerous significant associations were observed when comparing GA by group. Notably among these, CDKN2A/MTAP loss were more frequent in ERBB2wt versus ECDmut+ and amp+. ERBB3 GA were more frequent in ECDmut+ and KDmut+ than ERBB2wt. TERT GA were more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. TOP2A amplification was significantly more common in ECDmut+ and amp+ versus ERBB2wt, and TP53 SV GA were significantly higher in ERBB2 amp+ versus ERBB2wt. Mean TMB levels were significantly higher in ECDmut+, KDmut+, and amp+ than in ERBB2wt. Apolipoprotein B mRNA-editing enzyme, catalytic polypeptides (APOBEC) signature was more frequent in ECDmut+, KDmut+, and amp+ versus ERBB2wt. No significant differences were observed in PD-L1 status between groups, while gLOH-high status was more common in amp+ versus ERBB2wt. MSI-high status was more frequent in KDmut+ versus ERBB2wt, and in ERBB2wt than in amp+.

Conclusions

We noted important differences in co-occurring GA in ERBB2-altered (ECDmut+, KDmut+, amp+) versus ERBB2wt UBC, as well as higher mean TMB and higher APOBEC mutational signature in the ERBB2-altered groups. Our results can help refine future clinical trial designs and elucidate possible response and resistance mechanisms for ERBB2-altered UBC.

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ERBB2改变的尿路上皮膀胱癌基因组改变的频率和性质

摘要背景人表皮生长因子-2（HER2）过表达是包括尿路上皮膀胱癌（UBC）在内的许多实体瘤的致癌驱动因素。此外，ERBB2基因的激活突变也被证明具有与ERBB2扩增类似的致癌作用。目的描述并比较ERBB2基因改变（突变、扩增）和ERBB2野生型UBC基因组改变（GA）的频率和性质。患者和方法使用基于混合捕获的综合分析检测方法，按ERBB2改变对9518例UBC病例进行分组，并评估所有类别的基因组改变（GA）、肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、全基因组杂合性缺失（gLOH）和基因组突变特征。PD-L1 的表达通过免疫组化法（Dako 22C3）进行检测。分类统计比较采用费雪精确检验。结果共有602例（6.3%）UBC病例具有ERBB2胞外域短变异（SV）GA（ECDmut+），253例（2.7%）具有ERBB2激酶域SV GA（KDmut+），866例（9.1%）具有ERBB2扩增（amp+），7797例（81.9%）为ERBB2野生型（wt）。ECDmut+ 的欧洲遗传血统高于 ERBB2wt。在按组别比较GA时，观察到许多重要的关联。其中值得注意的是，CDKN2A/MTAP丢失在ERBB2wt与ECDmut+和amp+中更为常见。与ERBB2wt相比，ERBB3 GA在ECDmut+和KDmut+中更为常见。与ERBB2wt相比，TERT GA在ECDmut+、KDmut+和amp+中更常见。TOP2A扩增在ECDmut+和amp+中明显多于ERBB2wt，TP53 SV GA在ERBB2 amp+中明显多于ERBB2wt。ECDmut+、KDmut+和amp+的平均TMB水平明显高于ERBB2wt。载脂蛋白 B mRNA 编辑酶催化多肽（APOBEC）特征在 ECDmut+、KDmut+ 和 amp+ 与 ERBB2wt 中更为常见。各组间的 PD-L1 状态无明显差异，而 gLOH-高状态在 amp+ 与 ERBB2wt 之间更为常见。KDmut+与ERBB2wt相比，ERBB2wt比amp+更常见，而KDmut+比ERBB2wt更常见。结论我们注意到，在ERBB2改变（ECDmut+、KDmut+、amp+）与ERBB2wt UBC中，并发GA存在重要差异，ERBB2改变组的平均TMB更高，APOBEC突变特征更高。我们的研究结果有助于完善未来的临床试验设计，并阐明ERBB2改变的UBC可能的反应和耐药机制。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Targeted Oncology 医学-肿瘤学

CiteScore

8.40

自引率

3.70%

发文量

审稿时长

>12 weeks

期刊介绍： Targeted Oncology addresses physicians and scientists committed to oncology and cancer research by providing a programme of articles on molecularly targeted pharmacotherapy in oncology. The journal includes: Original Research Articles on all aspects of molecularly targeted agents for the treatment of cancer, including immune checkpoint inhibitors and related approaches. Comprehensive narrative Review Articles and shorter Leading Articles discussing relevant clinically established as well as emerging agents and pathways. Current Opinion articles that place interesting areas in perspective. Therapy in Practice articles that provide a guide to the optimum management of a condition and highlight practical, clinically relevant considerations and recommendations. Systematic Reviews that use explicit, systematic methods as outlined by the PRISMA statement. Adis Drug Reviews of the properties and place in therapy of both newer and established targeted drugs in oncology.