Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma.
Somatic Mosaic Mutations in PPM1D and TP53 in the Blood of Women With Ovarian Carcinoma.
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DOI：
10.1001/jamaoncol.2015.6053
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发表时间：
2016-03
期刊：
影响因子：
28.4
通讯作者：
Birrer MJ
中科院分区：
文献类型：
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作者：
Swisher EM;Harrell MI;Norquist BM;Walsh T;Brady M;Lee M;Hershberg R;Kalli KR;Lankes H;Konnick EQ;Pritchard CC;Monk BJ;Chan JK;Burger R;Kaufmann SH;Birrer MJ
已有报道在乳腺癌、肺癌和卵巢癌(OC)患者中发现PPM1D的体细胞马赛克突变，但因果关系尚未确定。为了验证体细胞马赛克突变与化疗暴露相关的假设，我们使用大规模平行测序方法对686例初发OC(n=412)或复发OC(n=274)患者的外周血单个核细胞(PBMC)突变进行了定量检测。PBMC体细胞嵌合体PPM1D突变频率与化疗前显著相关(P<；.001)，且化疗后年龄越大，复发OC优势比(OR)17.24；95%CI(6.80~43.69)；原发OC化疗后OR(4.82；95%CI，1.43~16.18)。相反，TP53的体细胞马赛克突变与化疗或年龄没有显著相关性。在13例确诊前的OC患者的序贯PBMC中，11例(84.6%)体细胞嵌合体PPM1D突变增加，2例(15.4%)出现TP53突变。化疗暴露和年龄影响PPM1D突变的PBMC克隆的积累。在检测外周血单核细胞体细胞马赛克突变与癌症风险的关系时，应注意控制化疗暴露和采血年龄。
Somatic mosaic mutations in PPM1D have been reported in patients with breast cancer, lung cancer, and ovarian cancer (OC), but cause or effect has not been established. To test the hypothesis that somatic mosaic mutations are associated with chemotherapy exposure, we used massively parallel sequencing to quantitate mutations in peripheral blood mononuclear cells (PBMCs) of 686 women with primary OC (n = 412) or relapsed OC (n = 274). The frequency of somatic mosaic PPM1D mutations in PBMCs was significantly associated with prior chemotherapy (P < .001), and, in patients exposed to chemotherapy, with older age at blood draw (recurrent OC odds ratio [OR], 17.24; 95%CI, 6.80–43.69; and primary OC postchemotherapy OR, 4.82; 95%CI, 1.43–16.18). In contrast, somatic mosaic mutations in TP53 were not significantly associated with chemotherapy or age. In sequential PBMC samples harvested from 13 patients with OC near diagnosis and after a median of 2 different chemotherapy regimens, somatic mosaic PPM1D mutations increased in 11 individuals (84.6%) and TP53 mutations appeared in 2 (15.4%). Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.