Yu Man, Shi Yurong, Zhang Fei, Zhou Yunli, Yang Yi, Wei Xiyin, Zhang Lin, Niu Ruifang
State Key Laboratory of Breast Cancer Prevention and Treatment, Cancer Hospital and Institute, Tianjin Medical University, Tianjin 300060, PR China.
J Biomed Sci. 2008 Jul;15(4):535-43. doi: 10.1007/s11373-007-9229-4. Epub 2007 Dec 22.
Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations. The non-coding displacement (D)-loop, especially a mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310), has been recently identified as a frequent hotspot of mutations in human neoplasia, including breast cancer. To further explore the sequence variations of mitochondrial D-loop region in familial breast cancer and their possible associations with breast cancer risk, PCR-SSCP and direct DNA sequencing methods were used to detect the variants of the mtDNA D-Loop in 23 familial breast cancer patients as well as three high-risk cancer families. Compared to that in sporadic breast tumors (53.3%, 16/30) and healthy blood donors (6.7%, 2/30), we identified a total of 126 sequence alterations in 23/23 (100%) of familial breast cancer patients, including eight novel nucleotide variants. Among these changes, A to G at nt.263, T to C at nt.489, T to C at nt.310, TC insertion at nt.311, CA deletion at nt.522, and C to G at nt.527 were highly frequent ones. In addition, among three high-risk cancer families, we found that individuals affected with breast cancer harbored more mtDNA sequence variants in mtDNA D310 area than other affected family members. Together, our data indicate that sequence variants within the mtDNA D-Loop region are frequent events in Chinese familial breast cancer patients. Some of these nucleotide abnormalities, particularly those in D310 segment, might be involved in the breast carcinogenesis and could be included in a panel of molecular biomarkers for cancer susceptibility early-detection strategy.
线粒体DNA（mtDNA）以其多态性和突变的高频率而闻名。非编码位移（D）环，尤其是303至315个核苷酸之间的单核苷酸重复序列（多聚C，D310），最近已被确定为人类肿瘤（包括乳腺癌）中常见的突变热点。为了进一步探索家族性乳腺癌中线粒体D环区域的序列变异及其与乳腺癌风险的可能关联，采用聚合酶链反应-单链构象多态性（PCR-SSCP）和直接DNA测序方法检测了23例家族性乳腺癌患者以及3个高危癌症家族中线粒体DNA D环的变异。与散发性乳腺肿瘤患者（53.3%，16/30）和健康献血者（6.7%，2/30）相比，我们在23/23（100%）的家族性乳腺癌患者中总共鉴定出126个序列改变，包括8个新的核苷酸变异。在这些变化中，第263位核苷酸处的A到G、第489位核苷酸处的T到C、第310位核苷酸处的T到C、第311位核苷酸处的TC插入、第522位核苷酸处的CA缺失以及第527位核苷酸处的C到G是高频变异。此外，在3个高危癌症家族中，我们发现患乳腺癌的个体在mtDNA D310区域比其他受影响的家庭成员携带更多的mtDNA序列变异。总之，我们的数据表明，mtDNA D环区域内的序列变异在中国家族性乳腺癌患者中很常见。其中一些核苷酸异常，特别是D310片段中的异常，可能参与了乳腺癌的发生，可纳入癌症易感性早期检测策略的一组分子生物标志物中。
