上皮性卵巢癌复发前后肿瘤组织中BRCA基因突变自身对照研究

Self-control study on BRCA gene mutations in 10 paired cases of primary and recurrent epithelial ovarian cancer

目的:探讨上皮性卵巢癌复发前后肿瘤组织中的乳腺癌易感基因(BRCA)突变状态及其临床意义。方法:收集上海交通大学医学院附属第九人民医院妇科2008年1月至2015年12月因上皮性卵巢癌行初次肿瘤细胞减灭术及复发后再次切除肿瘤的病例10例,应用全外显子测序技术检测患者原发和复发肿瘤组织中的基因突变情况,分析复发前后BRCA基因突变状态以及与铂类化疗药物敏感性的关系。结果:10例复发性上皮性卵巢癌患者中,2例(20%)同时携带致病性BRCA胚系和体细胞突变,2例(20%)携带致病性BRCA体细胞突变。在检测到的错义突变中,6例患者携带软件预测为可能致病的错义突变,4例患者未携带任何致病或可能致病BRCA突变。致病性BRCA胚系突变患者的肿瘤突变负荷高于无BRCA胚系突变患者(5.613±0.4255/Mb vs 0.7345±0.2859/Mb,P<0.0001)。携带BRCA体细胞突变的6例患者中,仅1例复发前后存在同一位点的BRCA体细胞突变,其余患者复发前后均存在不同的BRCA体细胞突变。BRCA突变主要发生在卵巢癌高发区(OCCR)以外区域,BRCA1突变主要位于exon 10,BRCA2突变主要位于exon 11。原发和复发肿瘤中均以C>T碱基转换为主。患者的BRCA突变状态与铂类敏感性无明显关联。结论:复发性上皮性卵巢癌组织中BRCA突变状态可与原发肿瘤不同。在一线化疗后及疾病进展中再次监测BRCA基因突变状态,可能对复发性卵巢癌的治疗方案设计有重要意义。

Objective:To investigate the breast cancer susceptibility gene(BRCA)mutation status in primary and recurrent epithelial ovarian cancer(EOC)and its clinical implications.Methods:Tumor samples of 10 paired primary and recurrent ovarian cancer were collected from January 2008 to December 2015 in Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine.Whole exome sequencing was performed to detect mutations.Data were analyzed to explore the relationship between primary tumor and recurrent tumor BRCA status,and the relationship between BRCA mutation and platinum-chemotherapy sensitivity.Results:Of the 10 cases,2 cases(20%)had both germline and somatic pathogenic BRCA mutations,2 cases(20%)had pathogenic BRCA somatic mutations.In silico analysis of missense mutations showed that 6 cases had potentially pathogenic missense mutations,and 4 cases did not carry any pathogenic or potentially pathogenic BRCA gene mutation.Cases with pathogenic BRCA germline mutations had higher tumor mutation burden than those without germline mutation(5.613±0.4255/Mb vs 0.7345±0.2859/Mb,P<0.0001).Of the 6 cases with BRCA somatic mutations,only 1 case had concordant BRCA somatic mutation in both the primary and recurrent tumors,while others had discordant BRCA somatic mutations.Most of the BRCA mutations were outside the region of ovarian cancer cluster region(OCCR).BRCA1 mutations mainly occurred in exon 10 while BRCA2 in exon 11.C>T mutation was the major transition in both primary and recurrent tumor.There was no obvious relationship between BRCA mutation status and platinum-chemotherapy sensitivity.Conclusions:BRCA status in paired primary and recurrent EOC may be discordant.This result suggests that BRCA re-detection after first-line chemotherapy and during disease progression should be of great importance,which may help make clinical decisions in the therapy for recurrent EOC.