Suh Ja Hee, Park Jeong Hwan, Lee Cheol, Moon Kyung Chul
Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
Department of Pathology, SMG-SNU Boramae Medical Center, Seoul, Korea.
Prostate. 2017 Oct;77(14):1438-1445. doi: 10.1002/pros.23405. Epub 2017 Aug 28.
Prostate cancer is considered to be highly heterogeneous, with various morphologic features and biologic behaviors. The TMPRSS2-ERG gene fusion is the most frequently observed genetic aberration in prostate cancer. The aim of this study was to elucidate the intrafocal heterogeneity of ERG gene fusion status.
ERG immunohistochemistry (IHC) was performed in samples from 168 prostate cancer patients who had undergone radical prostatectomy, and 40 cases showing ERG-positive IHC staining were selected for tissue microarray (TMA) construction. Two to six representative cores were selected from each tumor focus. In the cases with heterogeneous ERG IHC staining intensity, the areas showing different intensities were separately selected. Using the TMA blocks, IHC and fluorescence in situ hybridization (FISH) were conducted to evaluate the heterogeneity of ERG protein expression and ERG fusion gene patterns, respectively, in a single tumor focus. Heterogeneity of ERG IHC staining was defined as the simultaneous presence of negative and positive cores in the same tumor focus. Heterogeneity of ERG FISH was defined by the presence of cores with positive and negative FISH signals or cores with break-apart and interstitial deletion FISH signals in the same tumor focus.
A total of 202 TMA cores were isolated from 40 ERG-positive cases. Of the 202 total cores, 19 were negative for ERG IHC staining, and 46 showed 1+, 52 showed 2+, and 85 showed 3+ ERG staining intensity. Eleven cores were negative for ERG FISH signal, 119 cores showed ERG break-apart FISH signals, and the remaining 72 cores revealed interstitial deletion. Intrafocal heterogeneity of ERG IHC staining was found in 20% (8/40) of cases, and intrafocal heterogeneity of ERG gene fusion pattern was found in 32.5% (13/40) of cases.
In summary, this study showed significantly frequent intrafocal heterogeneity of ERG protein expression, gene fusion status and fusion pattern. This heterogeneity can be caused by the development of subclones during cancer progression or the intermingling of different tumors.
前列腺癌被认为具有高度异质性，具有多种形态学特征和生物学行为。TMPRSS2-ERG基因融合是前列腺癌中最常见的基因畸变。本研究的目的是阐明ERG基因融合状态的灶内异质性。
对168例行根治性前列腺切除术的前列腺癌患者的样本进行ERG免疫组织化学（IHC）检测，选取40例ERG免疫组化染色阳性的病例构建组织芯片（TMA）。从每个肿瘤灶中选取2至6个代表性组织芯。在ERG免疫组化染色强度不均一的病例中，分别选取显示不同强度的区域。利用TMA组织块，分别进行免疫组化和荧光原位杂交（FISH），以评估单个肿瘤灶中ERG蛋白表达和ERG融合基因模式的异质性。ERG免疫组化染色的异质性定义为同一肿瘤灶中同时存在阴性和阳性组织芯。ERG FISH的异质性定义为同一肿瘤灶中存在FISH信号阳性和阴性组织芯或存在断裂分离和间质缺失FISH信号的组织芯。
从40例ERG阳性病例中分离出202个TMA组织芯。在这202个组织芯中，19个ERG免疫组化染色阴性，46个显示1+的ERG染色强度、52个显示2+、85个显示3+。11个组织芯ERG FISH信号阴性，119个组织芯显示ERG断裂分离FISH信号，其余72个组织芯显示间质缺失。20%（8/40）的病例存在ERG免疫组化染色的灶内异质性，32.5%（13/40）的病例存在ERG基因融合模式的灶内异质性。
总之，本研究显示ERG蛋白表达、基因融合状态和融合模式的灶内异质性显著常见。这种异质性可能是由于癌症进展过程中亚克隆的发展或不同肿瘤的混合所致。
