Bergeron Alain, Picard Valérie, LaRue Hélène, Harel Francois, Hovington Hélène, Lacombe Louis, Fradet Yves
Centre de recherche en cancérologie de l'Université Laval, L'Hôtel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Québec, Canada.
Int J Cancer. 2009 Sep 15;125(6):1365-71. doi: 10.1002/ijc.24503.
Cancer-testis (CT) genes encode proteins that are ideal targets for cancer immunotherapy because of their restricted expression in normal tissues and frequent expression in cancers. We previously observed that MAGE-A9 was one of the CT genes most frequently expressed in bladder tumors. To confirm that observation and evaluate the potential prognostic value of MAGE-A9 protein, we analyzed its expression by immunohistochemistry in 493 primary bladder tumors and 33 lymph node metastases, in comparison with MAGE-A4 protein, also frequently expressed in bladder tumors. Overall, MAGE-A4 and MAGE-A9 were observed, respectively, in 38% and 63% of nonmuscle-invasive tumors, 48% and 57% of muscle-invasive tumors, 65% and 84% of carcinomas in situ and in 73% and 85% of lymph node metastases. Expression was associated with higher grade (MAGE-A4, p = 0.007; MAGE-A9, p = 0.012). In multivariate Cox regression analyses, expression of MAGE-A9 in pTa tumors was associated with recurrence (HR = 1.829; p = 0.010). In univariate analyses, MAGE-A4 expression in these same tumors was associated with progression to muscle-invasive cancer (HR = 7.417, p = 0.013). MAGE-A9 expression was even more predictive of progression as all tumors that progressed expressed this antigen. In muscle-invasive bladder tumors, no association was found between expression of either MAGE and bladder cancer-specific death. In conclusion, MAGE-A9 is a target of choice for bladder cancer immunotherapy as it is expressed in 60% of bladder tumors, predominantly high-grade tumors, and at higher frequency in pTis and metastatic tumors. Moreover, in pTa tumors, an immunotherapy targeting MAGE-A9 could be protective against recurrence and progression to more advanced cancer.
癌-睾丸（CT）基因编码的蛋白质是癌症免疫治疗的理想靶点，因为它们在正常组织中表达受限，而在癌症中频繁表达。我们之前观察到MAGE-A9是膀胱肿瘤中最常表达的CT基因之一。为了证实这一观察结果并评估MAGE-A9蛋白的潜在预后价值，我们通过免疫组织化学分析了493例原发性膀胱肿瘤和33例淋巴结转移灶中MAGE-A9的表达，并与同样在膀胱肿瘤中频繁表达的MAGE-A4蛋白进行了比较。总体而言，在非肌层浸润性肿瘤中，分别有38%和63%观察到MAGE-A4和MAGE-A9表达；在肌层浸润性肿瘤中，分别为48%和57%；原位癌中分别为65%和84%；淋巴结转移灶中分别为73%和85%。表达与更高分级相关（MAGE-A4，p = 0.007；MAGE-A9，p = 0.012）。在多变量Cox回归分析中，pTa肿瘤中MAGE-A9的表达与复发相关（HR = 1.829；p = 0.010）。在单变量分析中，这些相同肿瘤中MAGE-A4的表达与进展为肌层浸润性癌相关（HR = 7.417，p = 0.013）。MAGE-A9的表达对进展更具预测性，因为所有进展的肿瘤都表达这种抗原。在肌层浸润性膀胱肿瘤中，未发现MAGE的表达与膀胱癌特异性死亡之间存在关联。总之，MAGE-A9是膀胱癌免疫治疗的首选靶点，因为它在60%的膀胱肿瘤中表达，主要是高级别肿瘤，并且在pTis和转移性肿瘤中表达频率更高。此外，在pTa肿瘤中，针对MAGE-A9的免疫治疗可能对预防复发和进展为更晚期癌症具有保护作用。
