PDF(Pubmed)
Abstract：
Breast cancer is the commonest malignancy in women and the majority occurs sporadically with no hereditary predisposition. However, sporadic breast cancer has been studied less intensively than the hereditary form and to date hardly any predictive biomarkers exist for the former. Furthermore, although mitochondrial DNA variants have been reported to be associated with breast cancer, findings have been inconsistent across populations. Thus we carried out a case control study on sporadic breast cancer patients and healthy controls of Sinhalese ethnicity (N = 60 matched pairs) in order to characterize coding region variants associated with the disease and to identify any potential biomarkers. Mitochondrial genome was fully sequenced in 30 pairs and selected regions were sequenced in the remaining 30 pairs. Several in-silico tools were used to assess functional significance of the variants observed. A number of variants were identified among the patients and the controls. Missense variants identified were either polymorphisms or rare variants. Their prevalence did not significantly differ between patients and the healthy controls (matched for age, body mass index and menopausal status). MT-CYB, MT-ATP6 and MT-ND2 genes showed a higher mutation rate. A higher proportion of pre-menopausal patients carried missense and pathogenic variants. Unique combinations of missense variants were seen within genes and these occurred mostly in MT-ATP6 and MT-CYB genes. Such unique combinations that occurred exclusively among the patients were common in obese patients. Mitochondrial DNA variants may have a role in breast carcinogenesis in obesity and pre-menopause. Molecular dynamic simulations suggested the mutants, G78S in MT-CO3 gene and T146A in MT-ATP6 gene are likely to be more stable than their wild type counterparts.
摘要：
乳腺癌是女性最常见的恶性肿瘤，大多数是偶发的，没有遗传倾向。然而,散发性乳腺癌的研究不如遗传性乳腺癌，迄今为止几乎没有任何预测性生物标志物存在。此外，尽管据报道线粒体DNA变异与乳腺癌有关，不同人群的研究结果不一致.因此,我们对散发性乳腺癌患者和僧伽罗族的健康对照(N=60匹配对)进行了病例对照研究,以表征与疾病相关的编码区变体并鉴定任何潜在的生物标志物。线粒体基因组以30对完全测序，其余30对中的选定区域进行测序。使用几种计算机内工具来评估所观察到的变体的功能显著性。在患者和对照中鉴定了许多变体。鉴定的错义变体是多态性或罕见变体。他们的患病率在患者和健康对照之间没有显着差异(年龄匹配，体重指数和绝经状态）。MT-CYB,MT-ATP6和MT-ND2基因的突变率较高。绝经前患者携带错义和致病变异的比例更高。在基因中发现了错义变异的独特组合，这些变异主要发生在MT-ATP6和MT-CYB基因中。这种仅在患者中发生的独特组合在肥胖患者中很常见。线粒体DNA变异可能在肥胖和绝经前的乳腺癌发生中起作用。分子动力学模拟表明突变体，MT-CO3基因中的G78S和MT-ATP6基因中的T146A可能比它们的野生型对应物更稳定。
