Leary Jacob B, Enright Thomas, Bakaloudi Dimitra Rafailia, Basnet Alina, Bratslavsky Gennady, Jacob Joseph, Spiess Philippe E, Li Roger, Necchi Andrea, Kamat Ashish M, Pavlick Dean C, Danziger Natalie, Huang Richard S P, Lin Douglas I, Cheng Liang, Ross Jeffrey, Talukder Rafee, Grivas Petros
Department of Medicine, University of Washington, Seattle, WA, USA.
SUNY Upstate Medical University, Syracuse, NY, USA.
Target Oncol. 2024 May;19(3):447-458. doi: 10.1007/s11523-024-01056-x. Epub 2024 Apr 3.
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.
To describe and compare the frequency and nature of genomic alterations (GA) of ERBB2-altered (mutations, amplification) and ERBB2 wild-type UBC.
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.
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+.
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.
人表皮生长因子2（HER2）过表达是包括尿路上皮膀胱癌（UBC）在内的许多实体瘤中的致癌驱动因素。此外，已证明ERBB2基因中的激活突变发挥与ERBB2扩增类似的致癌作用。
描述并比较ERBB2改变（突变、扩增）和ERBB2野生型UBC的基因组改变（GA）的频率和性质。
使用基于杂交捕获的综合分析方法，将9518例UBC病例按ERBB2改变进行分组，并评估所有类型的基因组改变（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。通过免疫组织化学（Dako 22C3）检测PD-L1表达。使用Fisher精确检验进行分类统计比较。
共有602例（6.3%）UBC病例具有ERBB2细胞外结构域短变体（SV）GA（ECDmut+），253例（2.7%）病例具有ERBB2激酶结构域SV GA（KDmut+），866例（9.1%）病例有ERBB2扩增（amp+），7797例（81.9%）病例为ERBB2野生型（wt）。ECDmut+的欧洲遗传血统高于ERBB2wt。按组比较GA时观察到许多显著关联。其中特别值得注意的是，与ECDmut+和amp+相比，CDKN2A/MTAP缺失在ERBB2wt中更常见。与ERBB2wt相比，ERBB3 GA在ECDmut+和KDmut+中更常见。与ERBB2wt相比，TERT GA在ECDmut+、KDmut+和amp+中更常见。TOP2A扩增在ECDmut+和amp+中显著比ERBB2wt更常见，TP53 SV GA在ERBB2 amp+中显著高于ERBB2wt。ECDmut+、KDmut+和amp+中的平均TMB水平显著高于ERBB2wt。与ERBB2wt相比，载脂蛋白B mRNA编辑酶催化多肽（APOBEC）特征在ECDmut+、KDmut+和amp+中更常见。各组之间在PD-L1状态方面未观察到显著差异，而gLOH高状态在amp+中比ERBB2wt更常见。MSI高状态在KDmut+中比ERBBIwt更常见，在ERBB2wt中比amp+更常见。
我们注意到ERBB2改变（ECDmut+、KDmut+、amp+）与ERBB2wt UBC中同时发生的GA存在重要差异，以及ERBB2改变组中更高的平均TMB和更高的APOBEC突变特征。我们的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。
