Qu G, Dubeau L, Narayan A, Yu M C, Ehrlich M
Department of Biochemistry, Tulane Medical School, New Orleans, LA 70112, USA.
Mutat Res. 1999 Jan 25;423(1-2):91-101. doi: 10.1016/s0027-5107(98)00229-2.
Rearrangements in heterochromatin in the vicinity of the centromeres of chromosomes 1 and 16 are frequent in many types of cancer, including ovarian epithelial carcinomas. Satellite 2 DNA is the main sequence in the unusually long heterochromatin region adjacent to the centromere of each of these chromosomes. Rearrangements in these regions and hypomethylation of satellite 2 DNA are a characteristic feature of patients with a rare recessive genetic disease, ICF (immunodeficiency, centromeric region instability, and facial anomalies). In all normal tissues of postnatal somatic origin, satellite 2 DNA is highly methylated. We examined satellite 2 DNA methylation in ovarian tumors of different malignant potential, namely, ovarian cystadenomas, low malignant potential (LMP) tumors, and epithelial carcinomas. Most of the carcinomas and LMP tumors exhibited hypomethylation in satellite 2 DNA of both chromosomes 1 and 16. A comparison of methylation of these sequences in the three types of ovarian neoplasms demonstrated that there was a statistically significant correlation between the extent of this satellite DNA hypomethylation and the degree of malignancy (P<0.01). Also, there was a statistically significant association (P<0.005) between genome-wide hypomethylation and undermethylation of satellite 2 DNA among these 17 tumors. In addition, we found abnormal hypomethylation of satellite alpha DNA in the centromere of chromosome 1 in many of these tumors. Our findings are consistent with the hypothesis that one of the ways that genome-wide hypomethylation facilitates tumor development is that it often includes satellite hypomethylation which might predispose cells to structural and numerical chromosomal aberrations. Several of the proteins that bind to pericentromeric heterochromatin are known to be sensitive to the methylation status of their target sequences and so could be among the sensors for detecting abnormal demethylation and mediating effects on chromosome structure and stability.
在包括卵巢上皮癌在内的多种癌症中，1号和16号染色体着丝粒附近的异染色质重排十分常见。卫星2 DNA是这两条染色体着丝粒附近异常长的异染色质区域中的主要序列。这些区域的重排以及卫星2 DNA的低甲基化是患有罕见隐性遗传病ICF（免疫缺陷、着丝粒区域不稳定和面部异常）患者的一个特征。在出生后体细胞来源的所有正常组织中，卫星2 DNA高度甲基化。我们检测了不同恶性潜能的卵巢肿瘤，即卵巢囊腺瘤、低恶性潜能（LMP）肿瘤和上皮癌中卫星2 DNA的甲基化情况。大多数上皮癌和LMP肿瘤在1号和16号染色体的卫星2 DNA中均表现出低甲基化。对这三种类型卵巢肿瘤中这些序列甲基化情况的比较表明，这种卫星DNA低甲基化程度与恶性程度之间存在统计学上的显著相关性（P<0.01）。此外，在这17个肿瘤中，全基因组低甲基化与卫星2 DNA低甲基化之间存在统计学上的显著关联（P<0.005）。此外，我们在许多这些肿瘤中发现1号染色体着丝粒处的卫星α DNA存在异常低甲基化。我们的研究结果与以下假设一致，即全基因组低甲基化促进肿瘤发展的一种方式是它通常包括卫星低甲基化，这可能使细胞易发生结构和数量染色体畸变。已知几种与着丝粒周围异染色质结合的蛋白质对其靶序列的甲基化状态敏感，因此可能是检测异常去甲基化并介导对染色体结构和稳定性影响的传感器之一。
