855例前列腺癌患者错配修复基因胚系突变临床研究  

Mismatch repair gene germline mutations in patients with prostate cancer

作　　者：方邦伟 韦煜 潘剑 张挺维 叶定伟 朱耀 FANG Bangwei;WEI Yu;PAN Jian;ZHANG Tingwei;YE Dingwei;ZHU Yao(Department of Urology,Fudan University Shanghai Cancer Center,Department of Oncology,Shanghai Medical College Fudan University,Shanghai 200032,China)

机构地区：[1]复旦大学附属肿瘤医院泌尿外科复旦大学上海医学院肿瘤学系,上海200032

出　　处：《浙江大学学报（医学版）》2023年第2期133-138,共6页Journal of Zhejiang University(Medical Sciences)

基　　金：国家自然科学基金(82172621)。

摘　　要：目的:了解前列腺癌患者错配修复(MMR)基因胚系致病性突变携带情况及MMR基因突变患者的临床病理特征。方法:回顾性分析复旦大学附属肿瘤医院2018至2022年收治的855例前列腺癌患者的胚系基因测序数据,根据美国医学遗传学与基因组学学会遗传突变分类标准指南、Clinvar数据库和Intervar数据库评估突变的致病性。比较MMR基因突变患者(MMR^(+)组)、携带除外MMR基因的DNA损伤修复(DDR)基因胚系致病性突变患者(DDR^(+)MMR^(-)组)、未携带DDR基因胚系致病性突变患者(DDR^(-)组)的临床病理特征及对去势治疗的反应。结果:855例前列腺癌患者中,13例(1.52%)患者纳入MMR^(+)组,其中MLH1基因突变1例,MSH2基因突变6例,MSH6基因突变4例,PMS2基因突变2例;105例(11.9%)患者纳入DDR^(+)MMR^(-)组;737例(86.2%)患者纳入DDR^(-)组。与DDR^(-)组比较,MMR^(+)组患者初诊年龄小(P<0.05)、前列腺特异性抗原(PSA)水平低(P<0.01),而在格里森评分和TMN分期方面未发现明显的差异(均P>0.05)。MMR^(+)组、DDR^(+)MMR^(-)组和DDR^(-)组进展至去势抵抗阶段的用时中位数分别为8个月(95%CI:6个月~无法估计)、16个月(95%CI:12~32个月)、24个月(95%CI:21~27个月),其中MMR^(+)组达到去势抵抗状态的时间较DDR^(+)MMR^(-)组和DDR^(-)组明显缩短(均P<0.01),而DDR^(+)MMR^(-)组与DDR^(-)组之间差异无统计学意义(P>0.05)。结论:对早发、初诊PSA水平低却伴转移或去势治疗早期耐药的前列腺癌患者推荐进行MMR基因突变检测,以便为后续治疗选择提供参考。Objective:To investigate the prevalence of pathogenic germline mutations of mismatch repair(MMR)genes in prostate cancer patients and its relationship with clinicopathological characteristics.Methods:Germline sequencing data of 855 prostate cancer patients admitted in Fudan University Shanghai Cancer Center from 2018 to 2022were retrospectively analyzed.The pathogenicity of mutations was assessed according to the American College of Medical Genetics and Genomics(ACMG)standard guideline,Clinvar and Intervar databases.The clinicopathological characteristics and responses to castration treatment were compared among patients with MMR gene mutation(MMR^(+)group),patients with DNA damage repair(DDR)gene germline pathogenic mutation without MMR gene(DDR^(+)MMR^(-)group)and patients without DDR gene germline pathogenic mutation(DDRgroup).Results:Thirteen(1.52%)MMR^(+)patients were identified in 855 prostate cancer patients,including 1 case with MLH1 gene mutation,6 cases with MSH2 gene mutation,4 cases with MSH6 gene mutation and 2 cases with PMS2 gene mutation.105(11.9%)patients were identified as DDR gene positive(except MMR gene),and 737(86.2%)patients were DDR gene negative.Compared with DDR^(-)group,MMR^(+)group had lower age of onset(P<0.05)and initial prostate^(-)specific antigen(PSA)(P<0.01),while no significant differences were found between the two groups in Gleason score and TMN staging(both P>0.05).The median time to castration resistance was 8 months(95%CI:6 months^(-)not achieved),16 months(95%CI:12-32 months)and 24 months(95%CI:21^(-)27 months)for MMR^(+)group,DDR^(+)MMR^(-)group and DDR^(-)group,respectively.The time to castration resistance in MMR^(+)group was significantly shorter than that in DDR^(+)MMR^(-)group and DDR^(-)group(both P<0.01),while there was no significant difference between DDR^(+)MMR^(-)group and DDR^(-)group(P>0.05).Conclusion:MMR gene mutation testing is recommended for prostate cancer patients with early onset,low initial PSA,metastasis or early resistance to castration therapy.

关 键 词：前列腺癌 错配修复基因 DNA损伤修复基因 胚系突变 前列腺特异性抗原 

分 类 号：R737.25[医药卫生—肿瘤]