MMR基因突变的前列腺癌16例临床病理分析

Prostate cancer with MMR gene mutation:a clinicopathological analysis of 16 cases

目的总结DNA错配修复(mismatch repair,MMR)基因突变的前列腺癌的临床病理特征,探讨前列腺癌中MMR基因突变与蛋白表达缺失的相关性。方法收集16例MMR基因突变的前列腺癌患者的临床病理资料,采用免疫组化检测MMR蛋白(MLH1、PMS2、MSH2、MSH6)的表达,分析MMR基因突变与蛋白表达的相关性。结果16例MMR基因突变患者年龄55~79岁,中位年龄69岁;12例有远处转移,其中11例为骨转移,1例为多部位转移;12例为去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC)。组织学形态以经典的腺泡腺癌为主,其中7例伴有前列腺导管内癌成分,1例伴有导管腺癌成分,6例查见神经或血管侵犯,4例查见前列腺外累及。14例患者Gleason评分≥8分。二代测序(next-generation sequencing,NGS)检测结果显示,检出8例MMR基因致病突变(4例MSH2、3例MSH6和1例MLH3)和8例MMR基因临床意义不明变异。14例行MMR免疫组化检测仅5例MMR蛋白表达缺失,包括2例MSH2致病突变、2例MSH6致病突变和1例MSH6、MLH1临床意义不明变异。其中致病突变病例中NGS与免疫组化结果匹配率为4/5,而意义不明变异中NGS与免疫组化结果匹配率仅为1/8。结论MMR基因突变的前列腺癌常见于Gleason高分级、临床高分期和CRPC,常伴有导管内癌形态。前列腺癌中常见的MMR突变为MSH2和MSH6突变;MMR基因突变和蛋白表达缺失不完全匹配。

Purpose To summarize the clinicopathological features with DNA mismatch repair(MMR)gene mutation and to explore the correlation between MMR gene mutation and protein expression in prostate cancer.Methods Clinicopathological data of 16 prostate cancer patients with MMR gene mutation were collected,the expression of four MMR proteins(MLH1,PMS2,MSH2,MSH6)was detected by immunohistochemical staining,and correlation was analyzed between MMR gene mutation and protein expression.Results The 16 patients age ranged from 55 to 79 years,with median 69 years.12 patients presented with distant metastasis that included 11 cases with bone metastasis and 1 case with multiple metastases.12 patients were castration-resistant prostate cancer(CRPC).The histological characteristic was mainly classical prostatic acinar adenocarcinoma,including intraductal carcinoma(7 cases)and ductal adenocarcinoma(1 case).Nerve/vascular invasion and extraprostatic extension were detected in 6 cases and 4 cases,respectively.The Gleason score of 14 patients was≥8.Next generation sequencing results revealed that MMR gene pathogenic mutations in 8 cases(including of 4 MSH2,3 MSH6,and 1 MLH3),and the variants of unknown clinical significance(VUS)of MMR gene in another 8 cases.Immunohistochemical results revealed that MMR protein expression was absent in only 5 out of the 14 cases,which included 2 MSH2 pathogenic mutations,2 MSH6 pathogenic mutations,and one VUS of MSH6 and MLH1.The matching rate of NGS and IHC in pathogenic mutations was 4/5,while in mutations of VUS was only 1/8.Conclusion The presence of MMR gene mutations in prostate cancer is commonly observed in cases with high Gleason grade,advanced clinical stage,and CRPC patients,often accompanied by intraductal carcinoma.The predominant MMR gene alterations identified in prostate cancer are MSH2 and MSH6 mutations.The mutation of the MMR gene and the loss of protein expression in prostate cancer do not completely matched.