Mitochondrial: A Novel genetic modifier for breast cancer risk in Caucasian and A

描述（由申请人提供）：线粒体DNA（mtDNA）的体细胞突变被认为是癌症的标志。然而，线粒体DNA中的生殖系变异（多态性）在癌症发展中的作用在很大程度上是未知的。线粒体基因组在个体间具有高度多态性，并表现出显著的地理和种族差异。研究表明，某些mtDNA变异体可能通过增加活性氧（ROS）的产生而产生不利影响。随着时间的推移，这些不良影响的积累可能会增加个人的癌症风险。除了线粒体DNA的序列变异外，线粒体的拷贝数也可能通过干扰线粒体和细胞核之间的串扰从而改变细胞核DNA的稳定性来影响癌症风险。有人提出，每个细胞的线粒体拷贝数反映了未知遗传因素和氧化应激水平之间的基因-环境相互作用。然而，线粒体的拷贝数是否可以预测人类癌症的发展仍有待确定。线粒体DNA序列和拷贝数的变异性可能与乳腺癌极其相关，因为氧化应激已被认为在乳腺癌病因学中起重要作用。乳腺癌易感基因的发现已成为研究的热点。然而，迄今为止，已查明的情况很少。这种困境可能是由于这样一个事实，即一些易感等位基因可能不存在于核DNA，但在mtDNA。更有趣的是，mtDNA多态性的地理和种族差异可能对乳腺癌的种族差异有影响，因为非洲裔美国妇女患许多氧化应激相关疾病的风险不成比例地高，包括乳腺癌。因此，研究线粒体作为乳腺癌易感因素的作用可能具有重要意义。在目前的计划中，我们计划利用正在进行的病例对照研究（7 R 01 CA 100598）中收集的有价值的生物标本和数据，全面调查美国白人（CA）和非洲裔美国人（AA）妇女中mtDNA多态性/单倍型群与乳腺癌风险之间的关系。我们还将研究线粒体拷贝数与乳腺癌风险之间的关系。在进一步的分析中，我们将研究线粒体DNA多态性/单倍型群和线粒体拷贝数是否与乳腺癌的侵袭性临床特征相关。由于拟议的研究是嵌套在一个正在进行的研究，目标可以在一个及时和成本效益的方式解决。该研究将进一步了解导致乳腺癌发展的遗传事件;探索线粒体，ROS和乳腺癌之间的遗传基础;找到乳腺癌种族差异的线索，并最终提供一种识别最有可能发展乳腺癌的亚组的方法。然后，这些个体可以成为特定干预计划的目标，如化学预防和饮食调整。

DESCRIPTION (provided by applicant): Somatic mutations in mitochondrial DNA (mtDNA) have been regarded as a hallmark of cancer. However, the role of germline variations (polymorphisms) in mtDNA in cancer development is largely unknown. The mitochondrial genome is highly polymorphic among individuals and exhibits significant geographic and racial difference. It has been suggested that some mtDNA variants could have adverse effect by increase the generation of reactive oxygen species (ROS). The accumulation of those adverse effects over time may increase individual's cancer risk. Besides the sequence variations in mtDNA, the copy number of mitochondria might also affect cancer risk by disturbing crosstalk between mitochondrial and nucleus and consequently altering nuclear DNA stability. It has been proposed that the copy number of mitochondria per cell reflects the gene-environmental interactions between unknown hereditary factors and levels of oxidative stress. However, whether the copy number of mitochondria could be a predictor of human cancer development remains to be determined. Variability in MtDNA sequence and copy number of mitochondria might be extremely relevant to breast cancer because oxidative stress has been suggested to play a significant role in breast cancer etiology. Considerable efforts have been made to discover breast cancer susceptibility genes. However, few have been identified to date. The dilemma might be due to the fact that some of the susceptibility alleles might not reside in nuclear DNA, but in mtDNA. More intriguingly, the geographic and racial difference of mtDNA polymorphisms might have implications in breast cancer racial disparity because African American women are at disproportionately high risk for many oxidative stress-related medical conditions, including breast cancer. Therefore, the investigation of the role of mitochondrial as a predisposition factor of breast cancer could have significant impact. In current proposal, we plan to utilize the valuable biospecimens and data collected through an ongoing case-control study (7R01CA100598) to comprehensively investigate the associations between mtDNA polymorphisms/haplogroups and breast cancer risk in both Caucasian American (CA) and African American (AA) women. We will also examine the associations between the copy number of mitochondria and breast cancer risk. In further analysis, we will study whether mtDNA polymorphisms/haplogroups and copy number of mitochondria are associated with aggressive clinical characteristics of breast cancer. Because the proposed research is nested within an ongoing study, the objectives can be addressed in a timely and cost effective manner. The study will further our understanding of the genetic events leading to the development of breast cancer; explore the genetic basis linking mitochondrial, ROS and breast cancer; find the clues for breast cancer racial disparity, and eventually provide a means of identifying a subgroup that are most likely to develop breast cancer. Such individuals may then be targeted for specific intervention programs such as chemoprevention and dietary modification.