Aumayr Klaus, Klatte Tobias, Neudert Barbara, Birner Peter, Shariat Shahrokh, Schmidinger Manuela, Susani Martin, Haitel Andrea
Department of Pathology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
Department of Urology, Medical University of Vienna, Vienna, Austria.
Pathol Oncol Res. 2018 Jul;24(3):575-581. doi: 10.1007/s12253-017-0260-0. Epub 2017 Jul 28.
HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.
HER2作为一种潜在的治疗靶点，已被报道在尿路上皮癌中存在扩增。由于拓扑异构酶IIα（TOP2A）基因位于17号染色体q12 - q21上靠近HER2基因的位置，它经常与HER2扩增一起共扩增或缺失。本研究的目的是评估HER2和TOP2A基因扩增以及蛋白表达对上尿路尿路上皮癌（UTUC）预后的影响。对81例行根治性肾输尿管切除术的UTUC患者评估了HER2和TOP2A基因扩增及蛋白表达。对福尔马林固定、石蜡包埋的样本进行免疫组织化学和显色原位杂交检测。在81例病例中有27例（33%）观察到HER2蛋白表达，其中8例表现出HER2扩增。其中1例有额外的17号染色体多体性，而在67例HER2未扩增的病例中有6例显示17号染色体多体性。发现4例HER2和TOP2A共扩增，3例仅显示HER2扩增，20例仅显示TOP2A扩增。HER2免疫组化过表达与高级别肿瘤（p = 0.001）、非器官局限性癌（p = 0.017）、HER2扩增（p < 0.00001）和TOP2A扩增（p = 0.016）相关。HER2扩增与更高的肿瘤分级（p = 0.001）和淋巴结转移（p = 0.003）相关。TOP2A免疫组化阳性与更高的肿瘤分级（p = 0.0004）、TOP2A扩增（p = 0.0003）、17号染色体多体性（p = 0.035）和HER2免疫组化过表达（p = 0.28）显著相关，而所有肿瘤分期类别与HER2扩增仍无关联。TOP2A扩增在高级别、高肿瘤分期、17号染色体多体性和远处转移的肿瘤中分别显著更常见（p = 0.015；p = 0.042；p = 0.032；p = 0.011）。在单因素分析中，HER2免疫组化阳性、TOP2A扩增和17号染色体多体性与术后不良临床结局相关。HER2免疫组化过表达和TOP2A扩增与具有生物学侵袭性的UTUC特征相关。HER2和TOP2A的过表达和/或扩增有助于识别可能从靶向治疗中获益的患者。
