Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma
Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma
复制标题
DOI：
10.1200/jco.2018.78.5204
复制
发表时间：
2018-10-01
影响因子：
45.3
通讯作者：
Churpek, Jane E.
中科院分区：
文献类型：
--
作者：
Panou, Vasiliki;Gadiraju, Meghana;Churpek, Jane E.
目的本研究的目的是确定恶性间皮瘤（MM）患者种系癌易感突变的患病率和临床预测因素。方法对198例胸膜、腹膜和阴道膜mm患者的生殖系DNA进行85个癌易感基因的靶向捕获和下一代测序。结果在198例患者中，23例（12%）患者的13个基因中鉴定出24个突变。BAP1突变最为常见（n = 6; 25%）。其余的是涉及DNA损伤感知和修复（n = 14）、氧感知（n = 2）、核内体运输（n = 1）和细胞生长（n = 1）的基因。胸膜部位（比值比[OR]， 0.23; 95% CI, 0.10 ~ 0.58; P < 0.01）、石棉暴露（OR, 0.28; 95% CI, 0.11 ~ 0.72; P < 0.01）和年龄较大（OR, 0.95; 95% CI, 0.92 ~ 0.99; P = 0.01）与携带种系突变的几率降低相关，而第二次癌症诊断（OR, 3.33; 95% CI, 1.22 ~ 9.07; P = 0.02）显著增加了携带种系突变的几率。携带突变的几率BAP1(或者,1658;95%可信区间,199年到76224年;P <措施),BRCA2(或5;95%置信区间,1.0至14.7;P = 03), CDKN2A(或者,53;95%置信区间,6到249;P <措施),TMEM127(或者,88;95%可信区间,1.7至1105;P = . 01), VHL(或者,51;95%置信区间,1.1至453;P = .02点),和WT1(或者20;95%置信区间,0.5至135;P = .049)毫米的情况下显著高于非癌控制人口。肿瘤测序发现同源重组通路基因突变的比例为52% （n = 29 / 54）。结论相当比例的MM患者携带癌易感基因种系突变，特别是那些腹膜MM、石棉接触较少、年龄小、第二次癌症诊断的患者。这些数据为MM患者的临床种系基因检测提供了支持，并为进一步研究MM的同源重组途径提供了依据。
PurposeThe aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM).MethodsWe performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM.ResultsTwenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54).ConclusionA significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.