Suehiro Yutaka, Wong Chi Wai, Chirieac Lucian R, Kondo Yutaka, Shen Lanlan, Webb C Renee, Chan Yee Wai, Chan Annie S Y, Chan Tsun Leung, Wu Tsung-Teh, Rashid Asif, Hamanaka Yuichiro, Hinoda Yuji, Shannon Rhonda L, Wang Xuemei, Morris Jeffrey, Issa Jean-Pierre J, Yuen Siu Tsan, Leung Suet Yi, Hamilton Stanley R
Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Clin Cancer Res. 2008 May 1;14(9):2560-9. doi: 10.1158/1078-0432.CCR-07-1802.
Early events in colorectal tumorigenesis include mutation of the adenomatous polyposis coli (APC) gene and epigenetic hypermethylation with transcriptional silencing of the O(6)-methylguanine DNA methyltransferase (MGMT), human mut L homologue 1 (hMLH1), and P16/CDKN2A genes. Epigenetic alterations affect genetic events: Loss of MGMT via hypermethylation reportedly predisposes to guanine-to-adenine or cytosine-to-thymine (G:C-->A:T) transition mutations in KRAS and P53, and silencing of hMLH1 leads to high levels of microsatellite instability (MSI-H)/mutator phenotype, suggesting that epigenetic-genetic subtypes exist.
We evaluated the relationships of aberrant methylation of APC, MGMT, hMLH1, P16, N33, and five MINTs to mutations in APC, KRAS, BRAF, and P53 in 208 colorectal carcinomas.
We found that APC hypermethylation was age related (P = 0.04), in contrast to the other genes, and did not cluster with CpG island methylator phenotype (CIMP) markers. Hypermethylation of APC concurrently with either MGMT or hMLH1 was strongly associated with occurrence of G-to-A transitions in APC [odds ratio (OR), 26.8; P < 0.0002 from multivariable logic regression model], but C-to-T transitions had no associations. There was no relationship of hypermethylation of any gene, including MGMT, with G-to-A or C-to-T transitions in KRAS or P53, although APC hypermethylation was associated with P53 mutation (P < 0.0002). CIMP with MSI-H due to hMLH1 hypermethylation, or CIMP with loss of MGMT expression in non-MSI-H tumors, was associated with BRAF mutation (OR, 4.5; P < 0.0002). CIMP was also associated with BRAF V600E T-to-A transversion (OR, 48.5; P < 0.0002).
Our findings suggest that the heterogeneous epigenetic dysregulation of promoter methylation in various genes is interrelated with the occurrence of mutations, as manifested in epigenetic-genetic subgroups of tumors.
结直肠癌发生的早期事件包括腺瘤性息肉病 coli（APC）基因的突变以及 O(6)-甲基鸟嘌呤 DNA 甲基转移酶（MGMT）、人 mut L 同源物 1（hMLH1）和 P16/CDKN2A 基因的表观遗传高甲基化及转录沉默。表观遗传改变会影响基因事件：据报道，MGMT 通过高甲基化缺失易导致 KRAS 和 P53 基因发生鸟嘌呤到腺嘌呤或胞嘧啶到胸腺嘧啶（G:C→A:T）的转换突变，而 hMLH1 的沉默会导致高水平的微卫星不稳定性（MSI-H）/突变体表型，这表明存在表观遗传-基因亚型。
我们评估了 208 例结直肠癌中 APC、MGMT、hMLH１、P16、N33 和五个 MINTs 的异常甲基化与 APC、KRAS、BRAF 和 P53 突变之间的关系。
我们发现，与其他基因不同，APC 高甲基化与年龄相关（P = 0.04），且不与 CpG 岛甲基化表型（CIMP）标记聚类。APC 与 MGMT 或 hMLH1 同时发生高甲基化与 APC 中 G 到 A 的转换发生密切相关[比值比（OR），26.8；多变量逻辑回归模型 P < 0.0002]，但 C 到 T 的转换无相关性。尽管 APC 高甲基化与 P53 突变相关（P < 0.0002），但包括 MGMT 在内的任何基因的高甲基化与 KRAS 或 P53 中的 G 到 A 或 C 到 T 的转换均无关系。由于 hMLH1 高甲基化导致的 MSI-H 的 CIMP 或非 MSI-H 肿瘤中 MGMT 表达缺失的 CIMP 与 BRAF 突变相关（OR，4.5；P < 0.0002）。CIMP 也与 BRAF V600E 的 T 到 A 颠换相关（OR, 48.5；P < 0.0002）。
我们的研究结果表明，各种基因启动子甲基化的异质性表观遗传失调与突变的发生相互关联，这在肿瘤的表观遗传-基因亚组中有所体现。
