249例高危和极高危非转移性前列腺癌患者胚系基因检测结果分析与解读

Analysis and interpretation of genetic testing results from 249 Chinese high to very-high risk non-metastatic prostate cancer patients

目的分析国内高危和极高危非转移性前列腺癌患者的胚系致病性突变,探讨胚系致病性突变携带者的临床病理特征。方法回顾性分析2018年1月至2020年12月于复旦大学附属肿瘤医院、四川大学华西医院、中山大学肿瘤防治中心接受胚系基因检测的249例高危和极高危非转移性列腺癌患者的资料。患者年龄为(66.7±9.2)岁,确诊时前列腺特异性抗原(PSA)中位值28.50(2.43~1481.11)ng/ml;T_(1~2)期84例(33.7%),T_(3~4)期98例(39.3%),T分期不明67例(26.9%);国际泌尿病理协会(ISUP)分级分组1~3组51例(20.5%),4~5组198例(79.5%)。高危和极高危定义参考美国国立综合癌症网络(NCCN)前列腺癌指南(2022年第1版)。高危79例,极高危170例。从患者外周血淋巴细胞提取胚系DNA,采用第二代测序技术进行基因panel检测。按照美国医学遗传学与基因组学/美国分子病理学协会(ACMG/AMP)2015版指南对胚系基因检测数据进行解读。聚焦16种前列腺癌遗传易感基因,分析胚系致病性突变率与患者临床病理特征的关系。进一步与东亚健康人群的胚系致病性突变率比较,分析与高危或极高危前列腺癌致病风险相关的胚系突变。结果本研究249例中共检出18个(7.2%)胚系致病性突变,分别由18例患者携带。有胚系突变患者一级亲属有恶性肿瘤病史的比率较无胚系突变者显著增高[50%(9/18)与13%(30/231),P<0.001],有胚系突变患者与无胚系突变患者的年龄[(68.2±9.3)岁与(66.6±9.2)岁]、PSA[中位值:40.68ng/ml与28.00ng/ml]、ISUP分级分组[4~5组:88.9%(16/18)与78.8%(182/231)]、T分期[T_(3~4)期:38.9%(7/18)与39.4%(91/231)]差异均无统计学意义(P>0.05)。18个胚系致病性突变位于8个基因上,分别为BRCA2(7例,38.9%)、MSH2(3例,16.7%)、PALB2(2例,11.1%)、ATM(2例,11.1%)、RAD51C(1例,5.6%)、PMS2(1例,5.6%)、MSH6(1例,5.6%)和HOXB13(1例,5.6%)。对249例患者的胚系致病性突变率与东亚健康人群的胚系致病性突变率进行比较,结果显示BRCA2(OR=11.1,95%CI 4.8~25.6,P<0.001)和MSH2(OR=43.5,95%CI 8.5~200.0,P<0.001)基因的胚系致病性突变可显著增加男性罹患高危或极高危前列腺癌的风险。结论本研究高危和极高危非转移性前列腺癌患者的胚系致病性突变率为7.2%,携带胚系BRCA2或MSH2基因致病性突变可显著增加男性罹患高危或极高危前列腺癌的风险。

Objective To analyze germline genetic testing in Chinese high-to very-high-risk non-metastatic prostate cancer patients.Methods This study included 249 Chinese patients with high-to very-high-risk non-metastatic prostate cancer for germline genetic testing,in Fudan University Shanghai Cancer Center,West China Hospital and Cancer Center of Sun Yat-sen University,from January 2018 to December 2022.High risk and very-high risk are termed according to National Comprehensive Cancer Network(NCCN)Prostate Cancer Guideline(2022 V1).The mean age of the patients was(66.7±9.2)years old and median PSA level was 28.50(ranging 2.43-1481.11)ng/ml.Within these 249 patients,84(33.7%)were T_(1-2),98(39.3%)were T_(3-4),while 67(26.9%)were unclear in T stage.Additionally,51 patients(20.5%)were classified into International Society of Urological Pathology(ISUP)grade group 1-3 group and 198 patients(79.5%)were in ISUP 4-5 group.Focusing on 16 genetic susceptibility genes for prostate cancer,we interpret the germline genetic testing data in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology(ACMG/AMP)guideline,clarify the germline pathogenic mutation rate and elucidate the clinicopathological characteristics of germline pathogenic mutation carriers.Results Among Chinese high-to very-high-risk non-metastatic prostate cancer patients,7.2%(18/249)had germline pathogenic mutations.Patients with mutations had a significantly higher proportion of first-degree relatives with a history of malignancy than those without mutations(50%vs.13%,P<0.001),but there was no difference in age of onset[(68.2±9.3)years vs.(66.6±9.2)years],PSA level(median:40.68 ng/ml vs.28.00 ng/ml),T stage[T_(3-4):38.9%(7/18)vs.39.4%(91/231)]and ISUP grade[group 4-5:88.9%(16/18)vs.78.8%(182/231)].Germline pathogenic mutations were observed in BRCA2(7 patients,38.9%),MSH2(3 patients,16.7%),PALB2(2 patients,11.1%),ATM(2 patients,11.1%),RAD51C(1 patient,5.6%),PMS2(1 patient,5.6%),MSH6(1 patient,5.6%)and HOXB13(1 patient,5.6%).By comparing with normal controls of East-Asian population,germline pathogenic mutations in BRCA2(OR=11.1,95%CI 4.8-25.6,P<0.001)and MSH2(OR=43.5,95%CI 8.5-200.0,P<0.001)can significantly increase the risk of developing high-to very-high-risk prostate cancer in Chinese males.Conclusions This study identified a germline pathogenic mutation rate of 7.2%in 249 Chinese patients with high-or very-high-risk non-metastatic prostate cancer.Carrying germline BRCA2 or MSH2 pathogenic mutations can significantly increase the risk of high-or very-high-risk prostate cancer in Chinese men.