Sharma Meenal, Yang Zhiming, Miyamoto Hiroshi
Department of Pathology and Laboratory Medicine.
Department of Urology.
Medicine (Baltimore). 2020 May;99(19):e20124. doi: 10.1097/MD.0000000000020124.
Recent studies have suggested an increased risk of prostate cancer in men with Lynch syndrome driven by germline mutations in mismatch repair (MMR) genes. However, the incidence and clinical implication of MMR deficiency in sporadic prostate cancers remain poorly understood. We immunohistochemically stained for MLH1, MSH2, MSH6, and PMS2 in a set of tissue microarray consisting of 220 radical prostatectomy specimens and evaluated the relationship between loss of their expression and available clinicopathological features. MLH1, MSH2, MSH6, and PMS2 were lost in 2 (0.9%), 6 (2.7%), 37 (16.8%), and 27 (12.3%) prostate cancers, respectively. Loss of at least 1 MMR protein was identified in 50 (22.7%) cases. There were no statistically significant associations between MMR deficiency and patient age, family history of prostate cancer, Gleason score, or pT/pN stage. Nonetheless, the levels of preoperative prostate-specific antigen (PSA) were significantly (P = .015) higher in patients with MMR deficiency (mean ± SD: 9.12 ± 9.01 ng/mL) than in those without abnormal MMR (5.76 ± 3.17 ng/mL). There were 15 (6.8%) cases showing loss of at least 2 MMR proteins, which was not significantly associated with PSA level or tumor grade/stage. Additionally, 5 and 2 cases showed losses of at least 3 MMR proteins and all 4 proteins, respectively. Kaplan-Meier analysis revealed no significant associations between loss of MLH1 (P = .373), MSH2 (P = .348), MSH6 (P = .946), or PMS2 (P = .681), or at least 1 (P = .477), 2 (P = .486), or 3 (P = .352) MMR proteins and biochemical recurrence. Further analyses of the data on programmed death-ligand 1 (PD-L1) expression previously stained in the same set of tissue microarray demonstrated associations between loss of ≥2 MMR proteins and a higher rate of PD-L1 expression in cancer cells (17.2% vs 5.2%; P = .033) as well as between cases showing both loss of ≥1 MMR protein(s) and PD-L1 expression in tumor-infiltrating immune cells vs a higher risk of biochemical recurrence (P = .045). MMR protein loss was seen in a subset of prostate cancers. Interestingly, it was associated with significantly higher levels of PSA. Moreover, immunohistochemical detection of MMR proteins together with other proteins, such as PD-L1, might be helpful in predicting tumor recurrence following radical prostatectomy.
近期研究表明，错配修复（MMR）基因的种系突变会使林奇综合征男性患前列腺癌的风险增加。然而，散发性前列腺癌中MMR缺陷的发生率及临床意义仍知之甚少。我们对一组由220份根治性前列腺切除术标本组成的组织芯片进行MLH1、MSH2、MSH6和PMS2免疫组化染色，并评估其表达缺失与可用临床病理特征之间的关系。MLH1、MSH2、MSH6和PMS2在前列腺癌中的缺失率分别为2例（0.9%）、6例（2.7%）、37例（16.8%）和27例（12.3%）。50例（22.7%）病例中发现至少1种MMR蛋白缺失。MMR缺陷与患者年龄、前列腺癌家族史、 Gleason评分或pT/pN分期之间无统计学显著关联。尽管如此，MMR缺陷患者（均值±标准差：9.12±9.01 ng/mL）术前前列腺特异性抗原（PSA）水平显著高于（P = 0.015）MMR无异常的患者（5.76±3.17 ng/mL）。有15例（6.8%）病例显示至少2种MMR蛋白缺失，这与PSA水平或肿瘤分级/分期无显著关联。此外，分别有5例和2例显示至少3种和全部4种MMR蛋白缺失。Kaplan-Meier分析显示，MLH1缺失（P = 0.373）、MSH2缺失（P = 0.348）、MSH6缺失（P = 0.946）或PMS2缺失（P = 0.681），或至少1种（P = 0.477）、2种（P = 0.486）或3种（P = 0.352）MMR蛋白缺失与生化复发之间无显著关联。对同一组组织芯片中先前染色的程序性死亡配体1（PD-L1）表达数据的进一步分析表明，≥2种MMR蛋白缺失与癌细胞中更高的PD-L1表达率相关（17.2%对5.2%；P = 0.033），以及在肿瘤浸润免疫细胞中显示至少1种MMR蛋白缺失且伴有PD-L1表达的病例与更高的生化复发风险相关（P = 0.045）。在一部分前列腺癌中可见MMR蛋白缺失。有趣的是，它与显著更高的PSA水平相关。此外，MMR蛋白与其他蛋白（如PD-L1）一起进行免疫组化检测可能有助于预测根治性前列腺切除术后的肿瘤复发。
