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，mtDNA的种系变异（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之间具有高度多态性，并表现出显著的地理和种族差异。有人认为，一些mtDNA变异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患癌症的风险。除了mtDNA的序列变异外，线粒体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核DNA的稳定性而影响癌症风险。有人提出，每个细胞线粒体的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。MtDNA序列和线粒体拷贝数的变异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中起重要作用。在发现乳腺癌易感基因方面已经作出了相当大的努力。然而，到目前为止，很少有人被确认。这种困境可能是由于一些易感等位基因可能不存在于核DNA中，而存在于mtDNA中。更有趣的是，mtDNA多态性的地理和种族差异可能会影响乳腺癌的种族差异，因为非裔美国妇女患许多与氧化应激相关的疾病（包括乳腺癌）的风险过高。因此，研究线粒体作为乳腺癌易感因素的作用具有重要意义。在目前的提案中，我们计划利用正在进行的病例对照研究（7R01CA100598）收集的有价值的生物标本和数据，全面研究高加索美国人（CA）和非洲裔美国人（AA）女性mtDNA多态性/单倍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/单倍群和线粒体拷贝数是否与乳腺癌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，目标可以解决在一个及时和成本效益的方式。这项研究将进一步加深我们对导致乳腺癌发展的遗传事件的理解；探索线粒体、活性氧和乳腺癌之间的遗传基础；找到乳腺癌种族差异的线索，并最终提供一种方法来确定最有可能患乳腺癌的亚群体。这些人可能会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. PUBLIC HEALTH RELEVANCE: NARRATIVE Given the fact that mitochondrial produces energy and generate ROS, inherited variations in mtDNA might represent a newly described mechanism of cancer predisposition. Inherited variations in mtDNA may be extremely relevant for breast cancer, as oxidative stress has consistently been regarded as a risk factor for breast cancer. 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. From a clinical perspective, the long-term application of this information to risk assessment and thus to the prevention and early detection of breast cancer in families as well as population will be significant.