Darvishi Katayoon, Sharma Swarkar, Bhat Audesh K, Rai Ekta, Bamezai R N K
National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
Cancer Lett. 2007 May 8;249(2):249-55. doi: 10.1016/j.canlet.2006.09.005. Epub 2006 Nov 1.
Mitochondria are the major source of Reactive Oxygen Species (ROS) and mtDNA G10398A (Ala-->Thr) polymorphism, proposed to be involved in increased ROS production, has been shown in association with invasive breast cancer in African-American (AA) women [J.A. Canter, A.R. Kallianpur, F.F. Parl, R.C. Millikan, Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 65 (2005) 8028-8033] and prostate cancer in AA men [M.P. Mims, T.G. Hayes, S. Zheng, S.M. Leal, A. Frolov, M.M. Ittmann, et al., Mitochondrial DNA G10398A polymorphism and invasive breast cancer in African-American women, Cancer Res. 66 (2006) 1880; author reply 1880-1881]. The role of mitochondria, however, in cancer development has been in question recently [A. Salas, Y.G. Yao, V. Macaulay, A. Vega, A. Carracedo, H.J. Bandelt, A critical reassessment of the role of mitochondria in tumorigenesis, PLoS Med. 2 (2005) e296], which has made it pertinent to analyze the data and test the hypotheses by conducting fresh case-control studies. This study, therefore, makes an attempt to validate the exclusive presence of mtG10398A (Ala-->Thr) polymorphism in a haplotype constituting mtDNA haplogroup N and its sublineages, imparting this group a higher risk for breast cancer, based on the re-analyses of approximately 1000 complete human mtDNA sequences worldwide and collated information on 2334 individuals belonging to 18 regions in India. The conclusion drawn of mt10398A allele providing a risk towards cancer is confirmed in a case-control comparison study of 124 sporadic breast cancer patients and 273 controls; and 55 squamous cell carcinoma of esophagus, ESCC, and 163 controls, matched for age, ethnicity and sex from north India. It is further apparent from the study that such a mtDNA polymorphism background provides a higher risk for the cancers of the tissues which could be affected by environmental insults directly as in the ESCC, observed with a high acquired (somatic) rate of mutation in p53 when compared to the breast cancer, suggesting that the mtDNA variants that arose as energetic adaptations, influence our health differentially under different environment conditions and a given genetic background of the mt genome.
线粒体是活性氧（ROS）的主要来源，而线粒体DNA G10398A（丙氨酸→苏氨酸）多态性被认为与ROS生成增加有关，已被证明与非裔美国（AA）女性的浸润性乳腺癌相关[J.A. Canter，A.R. Kallianpur，F.F. Parl，R.C. Millikan，《非裔美国女性线粒体DNA G10398A多态性与浸润性乳腺癌》，《癌症研究》65（2005）8028 - 8033]以及AA男性的前列腺癌相关[M.P. Mims，T.G. Hayes，S. Zheng，S.M. Leal，A. Frolov，M.M. Ittmann等，《非裔美国女性线粒体DNA G10398A多态性与浸润性乳腺癌》，《癌症研究》66（2006）1880；作者回复1880 - 1881]。然而，线粒体在癌症发展中的作用最近受到了质疑[A. Salas，Y.G. Yao，V. Macaulay，A. Vega，A. Carracedo，H.J. Bandelt，《对线粒体在肿瘤发生中作用的批判性重新评估》，《公共科学图书馆·医学》2（2005）e296]，这使得通过开展新的病例对照研究来分析数据并检验假设变得很有必要。因此，本研究试图通过对全球约1000条完整人类线粒体DNA序列进行重新分析以及整理来自印度18个地区的2334名个体的信息，来验证构成线粒体DNA单倍群N及其亚谱系的单倍型中mtG10398A（丙氨酸→苏氨酸）多态性的独特存在，该单倍群赋予了患乳腺癌更高的风险。在一项对124例散发性乳腺癌患者和273名对照进行的病例对照比较研究中，以及对来自印度北部的55例食管鳞状细胞癌（ESCC）患者和163名年龄、种族和性别相匹配的对照进行的研究中，证实了mt10398A等位基因会增加患癌风险。该研究还进一步表明，这样的线粒体DNA多态性背景会使那些可能直接受到环境损伤影响的组织患癌风险更高，如ESCC，与乳腺癌相比，ESCC中p53的获得性（体细胞）突变率很高，这表明作为能量适应而出现的线粒体DNA变异，在不同环境条件和线粒体基因组特定遗传背景下对我们健康的影响存在差异。
