The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom. Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom.
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.
Cancer Res. 2015 Jul 15;75(14):2844-50. doi: 10.1158/0008-5472.CAN-14-1692. Epub 2015 May 14.
Increased mitochondrial DNA (mtDNA) copy number in peripheral blood cells (PBC) has been associated with the risk of developing several tumor types. Here we evaluate sources of variation of this biomarker and its association with breast cancer risk in a prospective cohort study. mtDNA copy number was measured using quantitative real-time PCR on PBC DNA samples from participants in the UK-based Breakthrough Generations Study. Temporal and assay variation was evaluated in a serial study of 91 women, with two blood samples collected approximately 6-years apart. Then, associations with breast cancer risk factors and risk were evaluated in 1,108 cases and 1,099 controls using a nested case-control design. In the serial study, mtDNA copy number showed low assay variation but large temporal variation [assay intraclass correlation coefficient (ICC), 79.3%-87.9%; temporal ICC, 38.3%). Higher mtDNA copy number was significantly associated with younger age at blood collection, being premenopausal, having an older age at menopause, and never taking HRT, both in cases and controls. Based on measurements in a single blood sample taken on average 6 years before diagnosis, higher mtDNA copy number was associated with increased breast cancer risk [OR (95% CI) for highest versus lowest quartile, 1.37 (1.02-1.83); P trend = 0.007]. In conclusion, mtDNA copy number is associated with breast cancer risk and represents a promising biomarker for risk assessment. The relatively large temporal variation should be taken into account in future analyses.
外周血细胞（PBC）中线粒体 DNA（mtDNA）拷贝数的增加与几种肿瘤类型的发展风险相关。在这里，我们评估了这种生物标志物的变异来源及其与前瞻性队列研究中乳腺癌风险的关联。使用英国突破性世代研究中参与者的 PBC DNA 样本，通过定量实时 PCR 测量 mtDNA 拷贝数。在一项针对 91 名女性的系列研究中评估了时间和检测变异性，这些女性的两份血液样本大约相隔 6 年采集。然后，使用嵌套病例对照设计，在 1108 例病例和 1099 例对照中评估了 mtDNA 拷贝数与乳腺癌风险因素和风险的关联。在系列研究中，mtDNA 拷贝数显示出较低的检测变异性，但时间变异性较大[检测内类相关系数（ICC），79.3%-87.9%；时间 ICC，38.3%]。较高的 mtDNA 拷贝数与采血时年龄较小、绝经前、绝经年龄较大以及从未服用 HRT 显著相关，无论是在病例还是对照组中。基于平均在诊断前 6 年采集的单个血液样本的测量，较高的 mtDNA 拷贝数与乳腺癌风险增加相关[最高与最低四分位数的比值（95%CI），1.37（1.02-1.83）；趋势 P 值=0.007]。总之，mtDNA 拷贝数与乳腺癌风险相关，是评估风险的有前途的生物标志物。在未来的分析中应考虑到相对较大的时间变异性。
