Integrated analysis of chromosomal, microsatellite and epigenetic instability in colorectal cancer identifies specific associations between promoter methylation of pivotal tumour suppressor and DNA repair genes and specific chromosomal alterations
Integrated analysis of chromosomal, microsatellite and epigenetic instability in colorectal cancer identifies specific associations between promoter methylation of pivotal tumour suppressor and DNA repair genes and specific chromosomal alterations
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DOI：
10.1093/carcin/bgm270
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发表时间：
2008-02-01
期刊：
影响因子：
4.7
通讯作者：
van Engeland, Manon
中科院分区：
文献类型：
--
作者：
Derks, Sarah;Postma, Cindy;van Engeland, Manon
结直肠癌是一种复杂的异质性疾病，基因组不稳定性和DNA启动子甲基化在其中起重要作用。本研究旨在探讨染色体不稳定性(CIN)、微卫星不稳定性(MSI)与结直肠癌相关基因启动子甲基化的关系。因此，我们分别用比较基因组杂交和单核苷酸标记BAT-26对71例癌组织进行了CIN和MSI检测。用甲基化特异性聚合酶链式反应分析抑癌基因和DNA修复基因hMLH1、O-6-MGMT、APC、p14(ARF)、p16(INK4A)、RASSF1A、GATA-4、GATA-5和CHFR的启动子甲基化。这些综合分析表明，在CIN+CRC中，GATA-4和p16(INK4A)启动子甲基化分别与15q11-q21的染色体丢失和20q13的染色体增加呈负相关(P值分别为3.8×10(-2)和4.5×10(-2))。有趣的是，RASSF1A、GATA-4、GATA-5和CHFR启动子的甲基化以及较高的甲基化指数(MI)与8q23-QTER的染色体增益呈正相关(P值分别为1.5×10(-2)、3.8×10(-2)、3.9×10(-2)、4.9×10(-2)和8.2×10(-3))。MSI与BRAF突变、hMLH1、APC和p16(INK4a)启动子甲基化和高MI(甲基化基因总数)相关(P值分别为2.4×10(-2)、2.5×10(-3)、1.8×10(-2)、4.6×10(-2)和1.0×10(-2))。因此，我们得出结论，关键抑癌基因和DNA修复基因的启动子甲基化与结直肠癌染色体改变的特定模式有关，这与MSI肿瘤的甲基化模式不同。
Colorectal cancer (CRC) is a complex and heterogeneous disease in which genomic instability and DNA promoter methylation play important roles. The aim of this study was to investigate the relationship between chromosomal instability (CIN), microsatellite instability (MSI) and promoter methylation of CRC-associated genes. Therefore, 71 CRCs were analysed for CIN and MSI by comparative genomic hybridization and the mononucleotide marker BAT-26, respectively. Promoter methylation of the tumour suppressor and DNA repair genes hMLH1, O-6-MGMT, APC, p14(ARF), p16(INK4A), RASSF1A, GATA-4, GATA-5 and CHFR was analysed using methylation-specific polymerase chain reaction. These integrative analyses showed that in CIN+ CRCs, promoter methylation of GATA-4 and p16(INK4A) was inversely related to chromosomal loss at 15q11-q21 and gain at 20q13, respectively (P values: 3.8 x 10(-2) and 4.5 x 10(-2), respectively). Interestingly, promoter methylation of RASSF1A, GATA-4, GATA-5 and CHFR, as well as a high methylation index (MI), was positively related to chromosomal gain at 8q23-qter (P values: 1.5 x 10(-2), 3.8 x 10(-2), 3.9 x 10(-2), 4.9 x 10(-2) and 8.2 x 10(-3), respectively). MSI was associated with BRAF mutation, promoter methylation of hMLH1, APC and p16(INK4A) and a high MI (total number of methylated genes) (P values: 2.4 x 10(-2), 2.5 x 10(-3), 1.8 x 10(-2), 4.6 x 10(-2) and 1.0 x 10(-2), respectively). Therefore, we conclude that promoter methylation of pivotal tumour suppressor and DNA repair genes is associated with specific patterns of chromosomal changes in CRC, which are different from methylation patterns in MSI tumours.