Tranah Gregory J, Bugni James, Giovannucci Edward, Ma Jing, Fuchs Charles, Hines Lisa, Samson Leona, Hunter David J
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Cancer Causes Control. 2006 Jun;17(5):721-31. doi: 10.1007/s10552-006-0005-y.
O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6-position of guanine in DNA. Unrepaired O6-methylguanines result in G:C to A:T transitions in mutated K-ras and p53 in colorectal tumors. Two non-synonymous MGMT coding region variants, Leu84Phe and Ile143Val, lie in close proximity to the reactive 145Cys residue and to a conserved estrogen receptor interacting helix.
We assessed the association between the MGMT Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in two nested case-control studies: one each in the Nurses' Health Study (NHS) and the Physicians' Health Study (PHS) cohorts.
Among 197 female cases and 2,500 controls from the NHS, the variant 143Val allele was significantly associated with reduced risk of colorectal cancer [odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.33-0.80]. In women, statistically significant gene-environment interactions were found between the Leu84Phe polymorphism and alcohol intake (P = 0.03), BMI (P = 0.04) and postmenopausal hormone use (P = 0.03). The Leu84Phe and Ile143Val polymorphisms were not significantly associated with risk of colorectal cancer among 271 male cases and 451 controls from the PHS.
Our results suggest that the common Leu84Phe and Ile143Val polymorphisms in MGMT influence risk of colorectal cancer in women possibly through modulating estrogen receptor-dependent transcriptional activation, which has previously been shown to occur in response to DNA alkylation damage.
O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）可从DNA中鸟嘌呤的O6位去除诱变加合物。未修复的O6-甲基鸟嘌呤会导致结肠直肠癌中突变的K-ras和p53基因发生G:C到A:T的转换。两个非同义MGMT编码区变体，Leu84Phe和Ile143Val，紧邻反应性145Cys残基以及一个保守的雌激素受体相互作用螺旋。
在两项巢式病例对照研究中，我们评估了MGMT Leu84Phe和Ile143Val多态性与结直肠癌风险之间的关联：一项在护士健康研究（NHS）队列中进行，另一项在医生健康研究（PHS）队列中进行。
在NHS的197例女性病例和2500例对照中，143Val变体等位基因与结直肠癌风险降低显著相关[比值比（OR）=0.52，95%置信区间（CI）0.33 - 0.80]。在女性中，发现Leu84Phe多态性与酒精摄入量（P = 0.03）、体重指数（BMI，P = 0.04）和绝经后激素使用（P = 0.03）之间存在统计学上显著的基因-环境相互作用。在PHS的271例男性病例和451例对照中，Leu84Phe和Ile143Val多态性与结直肠癌风险无显著关联。
我们的结果表明，MGMT中常见的Leu84Phe和Ile143Val多态性可能通过调节雌激素受体依赖性转录激活来影响女性结直肠癌风险，此前已证明这种激活会在DNA烷基化损伤时发生。
