Somatic Mutations throughout the Entire Mitochondrial Genome Are Associated with Elevated PSA Levels in Prostate Cancer Patients
Somatic Mutations throughout the Entire Mitochondrial Genome Are Associated with Elevated PSA Levels in Prostate Cancer Patients
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DOI：
10.1016/j.ajhg.2010.11.001
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发表时间：
2010-12-10
影响因子：
9.8
通讯作者：
Kronenberg, Florian
中科院分区：
文献类型：
--
作者：
Kloss-Brandstaetter, Anita;Schaefer, Georg;Kronenberg, Florian
前列腺癌是西方国家最常见的男性癌症，其遗传病因复杂，疾病基因与环境因素的相互作用尚不清楚。体细胞线粒体DNA(MtDNA)突变的研究已经成为癌症研究的一个重要方面，因为这些突变可能具有功能后果和/或可能作为肿瘤检测和进展的生物传感器。我们从前列腺癌患者的30对大体解剖的癌和良性细胞中对整个线粒体基因组(16569bp)进行了测序，并比较了它们的遗传变异性。考虑到最近对新发现的线粒体DNA突变真实性的担忧，我们实施了一种高质量的线粒体DNA全基因组测序程序。此外，还对35例前列腺癌患者的线粒体基因MT-CO2、MT-CO3、MT-ATP6和MT-ND6进行了测序。我们在30名患者中的22名患者中总共发现了41个体细胞突变：这些突变中的大多数以前在人类系统发展史中从未观察到过。转移RNA(TRNA)的体细胞突变与PSA水平升高(14.25+/-5.44vs7.15+/-4.32 ng/ml；p=0.004)相关。异质性的程度和程度随着肿瘤活动性的增加而增加。总而言之，线粒体基因组中的体细胞突变是前列腺癌的常见事件。映射到线粒体tRNA、核糖体RNA和蛋白质编码基因的突变可能会损害线粒体内部发生的过程(如转录、RNA加工和翻译)，并可能最终影响氧化磷酸化。
The genetic etiology of prostate cancer, the most common form of male cancer in western countries, is complex and the interplay of disease genes with environmental factors is far from being understood. Studies on somatic mitochondrial DNA (mtDNA) mutations have become an important aspect of cancer research because these mutations might have functional consequences and/or might serve as biosensors for tumor detection and progression. We sequenced the entire mitochondrial genome (16,569 bp) from 30 prospectively collected pairs of macrodissected cancerous and benign cells from prostate cancer patients and compared their genetic variability. Given recent concerns regarding the authenticity of newly discovered mtDNA mutations, we implemented a high-quality procedure for mtDNA whole-genome sequencing. In addition, the mitochondrial genes MT-CO2, MT-CO3, MT-ATP6, and MT-ND6 were sequenced in further 35 paired samples from prostate cancer patients. We identified a total of 41 somatic mutations in 22 out of 30 patients: the majority of these mutations have not previously been observed in the human phylogeny. The presence of somatic mutations in transfer RNAs (tRNAs) was found to be associated with elevated PSA levels (14.25 +/- 5.44 versus 7.15 +/- 4.32 ng/ml; p = 0.004). The level and degree of heteroplasmy increased with increasing tumor activity. In summary, somatic mutations in the mitochondrial genome are frequent events in prostate cancer. Mutations mapping to mitochondrial tRNAs, ribosomal RNAs, and protein coding genes might impair processes that occur within the mitochondrial compartment (e.g., transcription, RNA processing, and translation) and might finally affect oxidative phosphorylation.