Velasco Alfredo, Corvalan Alejandro, Wistuba Ignacio I, Riquelme Erick, Chuaqui Rodrigo, Majerson Alejandro, Leach Fredrick S
Department of Urology, Pontificia Universidad Católica de Chile, Santiago, Chile.
Int J Cancer. 2008 Apr 15;122(8):1774-7. doi: 10.1002/ijc.23291.
We investigated mismatch repair (MMR) gene expression in testicular cancer as a molecular marker for clinical outcome (recurrence, response to chemotherapy and death) using protein expression and specific genetic alterations associated with the presence or absence of MMR activity. One hundred sixty-two cases of paraffin-embedded testis cancer specimens were subjected to immunohistochemical analysis using monoclonal antibody for MLH1 and MSH2 MMR proteins and genetic analysis using specific polymorphic markers. The degree of MMR immunoreactivity and genetic instability in the form of loss of heterozygosity (LOH) and/or microsatellite instability (MSI) were determined by comparing matched normal and tumor tissue. The degree of immunohistochemical staining for MMR expression was associated with a shorter time to tumor recurrence, resistance to chemotherapy and death. Furthermore, clinical relapse and cancer specific death was also associated with tumors exhibiting a high degree of MSI, p = 0.01 and 0.04, respectively. In contrast, LOH was not associated with recurrence, resistance to chemotherapy or death. Therefore, MMR expression defines testis cancers with distinct molecular properties and clinical behavior, such that tumors with decreased MMR immunostaining and/or increased frequency of MSI have a shorter time to recurrence and death despite chemotherapy.
我们利用与错配修复（MMR）活性的有无相关的蛋白表达和特定基因改变，研究了睾丸癌中MMR基因表达作为临床结局（复发、对化疗的反应和死亡）的分子标志物。对162例石蜡包埋的睾丸癌标本进行免疫组化分析，使用针对MLH1和MSH2 MMR蛋白的单克隆抗体，并使用特定的多态性标志物进行基因分析。通过比较匹配的正常组织和肿瘤组织，确定MMR免疫反应性程度以及以杂合性缺失（LOH）和/或微卫星不稳定性（MSI）形式存在的基因不稳定性。MMR表达的免疫组化染色程度与肿瘤复发时间缩短、对化疗的耐药性和死亡相关。此外，临床复发和癌症特异性死亡也分别与表现出高度MSI的肿瘤相关，p值分别为0.01和0.04。相比之下，LOH与复发、对化疗的耐药性或死亡无关。因此，MMR表达定义了具有不同分子特性和临床行为的睾丸癌，即MMR免疫染色降低和/或MSI频率增加的肿瘤，尽管接受了化疗，但复发和死亡时间更短。
