Morphological features of TMPRSS2-ERG gene fusion prostate cancer

The TMPRSS2-ETS fusion prostate cancers comprise 50-70% of the prostate-specific antigen (PSA)-screened hospital-based prostate cancers examined to date, making it perhaps the most common genetic rearrangement in human cancer. The most common variant involves androgen-regulated TMPRSS2 and ERG, both located on chromosome 21. Emerging data from our group and others suggests that TMPRSS2-ERG fusion prostate cancer is associated with higher tumour stage and prostate cancer-specific death. The goal of this study was to determine if this common somatic alteration is associated with a morphological phenotype. We assessed 253 prostate cancer cases for TMPRSS2-ERG fusion status using an ERG break-apart FISH assay. Blinded to gene fusion status, two reviewers assessed each tumour for presence or absence of eight morphological features. Statistical analysis was performed to look for significant associations between morphological features and TMPRSS2-ERG fusion status. Five morphological features were associated with TMPRSS2-ERG fusion prostate cancer: blue-tinged mucin, cribriform growth pattern, macronucleoli, intraductal tumour spread, and signet-ring cell features, all with p-values < 0.05. Only 24% (n=30/125) of tumours without any of these features displayed the TMPRSS2-ERG fusion. By comparison, 55% (n=38/69) of cases with one feature (RR=3.88), 86% (n=38/44) of cases with two features (RR=20.06), and 93% (n=14/15) of cases with three or more features (RR=44.33) were fusion positive (p<0.001). To our knowledge, this is the first study that demonstrates a significant link between a molecular alteration in prostate cancer and distinct phenotypic features. The strength of these findings is similar to microsatellite unstable colon cancer and breast cancer involving BRCA1 and BRCA2 mutations. The biological effect of TMPRSS2-ERG overexpression may drive pathways that favour these common morphological features that pathologists observe daily. These features may also be helpful in diagnosing TMPRSS2-ERG fusion prostate cancer, which may have both prognostic and therapeutic implications.     

前列腺癌中TMPRSS2-ERG融合基因和ERG蛋白表达及其意义

目的 探讨前列腺癌(prostate cancer,PC)中TMPRSS2-ERG(T-E)融合基因和ERG蛋白表达及其与各临床病理参数和预后的关系.方法 采用FISH和免疫组化技术分别检测145例PC穿刺标本中T-E融合基因和ERG蛋白的表达,以癌旁正常腺体为内对照.结果 145例PC中37例(25.5％)T-E融合基因阳性.T-E融合基因表达与患者年龄、术前血清PSA水平、Gleason评分、肿瘤有无远处转移和生存期均无相关性(P＞0.05).PC中ERG蛋白阳性率为24.8％ (36/145).ERG蛋白与术前血清PSA水平具有相关性(P＜0.05);与患者年龄、Gleason评分、肿瘤有无远处转移和患者生存期均无相关性.结论 T-E融合基因和ERG蛋白表达仅出现在PC中,而不出现于正常前列腺腺体,T-E融合基因和ERG蛋白可作为PC的特异性标志物.仅ERG蛋白表达与PSA水平相关,而T-E融合基因与临床病理参数和预后均无相关性.     

前列腺癌组织中TMPRSS2-ETS融合基因检测及其意义

近年学者发现,大多数前列腺癌中跨膜丝氨酸蛋白酶2(TMPRSS2)基因与ETS转录因子家族的ERG、ETV1或ETV4之间可以发生融合,形成融合基因TMPRSS2-ERG、-ETV1和-ETV4(此型极少见),且它们可能还是重要预后指标[1-3].为探讨中国人前列腺癌组织中TMPRSS2基因与ERG和ETV1基因的融合情况,我们采用逆转录聚合酶链反应(RT-PCR)对前列腺癌和前列腺良性增生(BPH)患者的融合基因进行了检测.     

TMPRSS2-ERG融合基因在转移性前列腺癌中的表达

目的 检测转移性前列腺癌中TMPRSS2-ERG基因融合的发生率,探讨ERG基因重排在前列腺癌进展中的作用.方法 收集32例由细针穿刺诊断的转移性前列腺癌,穿刺部位包括盆腔及远处淋巴结、肝、骨、甲状腺等,回顾相关临床病理学资料.免疫组织化学采用EnVision法标记前列腺特异性抗原、突触素和嗜铬粒素A.运用ERG分离断...     

The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers

Recent studies have revealed the presence of TMPRSS2-ERG gene fusion in both primary and metastatic prostate cancers. However, the relationship between primary and corresponding metastatic prostate cancers with respect to the status of this gene fusion remains unclear. Using fluorescence in situ hybridization, we evaluated the rearrangement of the ERG gene in the radical prostatectomy specimens and corresponding lymph node metastases from 19 patients with prostate cancer. The mean age of the patients was 61 years, and the median Gleason score in the radical prostatectomy specimens was 7 (4 + 3). Prostate cancer was unifocal in 6 cases and multifocal in 13 cases, including 10 with 2 foci and 3 with 3 foci. In the primary prostate cancers, rearrangement of the ERG gene was observed in 13 cases and associated with deletion of the 5' ERG gene in 8 cases. In the metastases, the ERG rearrangement was present in 10 cases and associated with deletion of the 5' ERG gene in 6 cases. In unifocal prostate cancers, the status of the ERG rearrangement was concordant between the primary prostate cancer and metastasis in 5 of 6 cases. In multifocal prostate cancer, despite a significant interfocal discordance, the status of the ERG rearrangement was concordant between the index (largest) primary tumor focus and metastasis in all 13 cases. Our study demonstrates a close relationship of the TMPRSS2-ERG gene fusion status between primary and metastatic prostate cancer. The concordance of the ERG gene rearrangement status between the index primary tumor focus and metastasis suggests that metastasis most likely arises from the index tumor focus in multifocal prostate cancer.     

TMPRSS2-ERG及MMP-9基因对前列腺癌侵袭性的影响

目的探讨TMPRSS2-ERG(T-E)及MMP-9基因在提高前列腺癌侵袭性方面的关联。方法分别使用FISH和RT-PCR方法检测转移性前列腺癌、局限性前列腺癌及良性前列腺增生患者组织中T-E和MMP-9基因的表达,制备抗ERG及MMP-9的siRNA并转染两种前列腺癌细胞系,采用Transwell实验检测转染siRNA后前列腺癌细胞的侵袭能力。结果 T-E融合基因的阳性率及MMP-9基因的相对表达量在3组间逐渐下降(P0.01),转移性前列腺癌组中两基因分别与Gleason评分(P0.05)及血清PSA水平(P0.05)呈正相关。转移性前列腺癌组T-E基因融合阳性的患者MMP-9基因表达显著高于T-E基因融合阴性者(P0.05),且两基因间表达呈正相关(r=0.875,P0.05)。下调ERG及MMP-9基因的表达分别能显著降低VCAP细胞(T-E融合基因阳性)和LNCa P细胞(T-E融合基因阴性)的侵袭性。结论 T-E融合基因和MMP-9基因在提高前列腺癌侵袭性方面有协同作用,但MMP-9可能不是T-E融合基因的关键靶基因。     

Clinical significance of TMPRSS4 in prostate cancer

Transmembrane protease serine 4 (TMPRSS4) is a type-II transmembrane serine protease that plays an important role in the migration of cancer cells. This study aimed to investigate both the expression of TMPRSS4 and its clinical significance in prostate cancer. The expression of TMPRSS4 was evaluated in 73 pairs of prostate cancer and adjacent non-cancerous tissues by immunohistochemistry. The level of TMPRSS4 in prostate cancer tissues was significantly higher than that in adjacent non-cancerous tissues. High TMPRSS4 expression was significantly associated with advanced TNM stage and LNM. No association between TMPRSS4 expression and progression-free survival was observed in all patients. Stratified analyses according to clinical features revealed that patients with low TMPRSS4 expression had poor prognosis compared with those with high TMPRSS4 expression in subjects not receiving neoadjuvant chemotherapy. In conclusion, TMPRSS4 showed abnormal expression in prostate cancer tissues. TMPRSS4 may be a potential prognostic biomarker for prostate cancer patients who did not undergo neoadjuvant chemotherapy.     

Relative 8q gain predicts disease-specific survival irrespective of the TMPRSS2-ERG fusion status in diagnostic biopsies of prostate cancer

Screening tools have greatly improved prostate cancer (PCa) detection, but the disease course is heterogeneous, and standard clinicopathological parameters do not fully discriminate aggressive from indolent tumors. To evaluate the prognostic value of the TMPRSS2-ERG fusion gene combined with chromosome arm 8q relative gain in diagnostic biopsies of PCa, we studied a consecutive series of 200 diagnostic needle biopsies from patients with 10-year disease-specific survival data. TMPRSS2-ERG fusion gene status and relative 8q gain were assessed by fluorescent in situ hybridization in whole formalin fixed paraffin-embedded biopsies. The TMPRSS2-ERG fusion gene was detected in 43.5% of PCa and was associated with lower Gleason score (P = 0.045), whereas relative 8q gain was present in 48% of PCa and was associated in high-Gleason score (P < 0.001). ERG rearrangement alone was not associated with clinical outcome, whereas relative 8q gain predicted worse disease-specific survival in PCa patients both with and without the TMPRSS2-ERG fusion gene (P < 0.001), independently of Gleason score, clinical stage, and treatment modality. We conclude that relative 8q gain in diagnostic needle biopsies is a poor prognostic factor independent of the TMPRSS2-ERG fusion gene status and of standard clinicopathological parameters.     

Testing mutual exclusivity of ETS rearranged prostate cancer

Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5' fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements.