Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
PLoS One. 2009 Nov 23;4(11):e7951. doi: 10.1371/journal.pone.0007951.
Exposure to energy restriction during childhood and adolescence is associated with a lower risk of developing colorectal cancer (CRC). Epigenetic dysregulation during this critical period of growth and development may be a mechanism to explain such observations. Within the Netherlands Cohort Study on diet and cancer, we investigated the association between early life energy restriction and risk of subsequent CRC characterized by the (promoter) CpG island methylation phenotype (CIMP).
METHODOLOGY/PRINCIPAL FINDINGS: Information on diet and risk factors was collected by baseline questionnaire (n = 120,856). Three indicators of exposure were assessed: place of residence during the Hunger Winter (1944-45) and World War II years (1940-44), and father's employment status during the Economic Depression (1932-40). Methylation specific PCR (MSP) on DNA from paraffin embedded tumor tissue was performed to determine CIMP status according to the Weisenberger markers. After 7.3 years of follow-up, 603 cases and 4631 sub-cohort members were available for analysis. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals for CIMP+ (27.7%) and CIMP- (72.3%) tumors according to the three time periods of energy restriction, adjusted for age and gender. Individuals exposed to severe famine during the Hunger Winter had a decreased risk of developing a tumor characterized by CIMP compared to those not exposed (HR 0.65, 95%CI: 0.45-0.92). Further categorizing individuals by an index of '0-1' '2-3' or '4-7' genes methylated in the promoter region suggested that exposure to the Hunger Winter was associated with the degree of promoter hypermethylation ('0-1 genes methylated' HR = 1.01, 95%CI:0.74-1.37; '2-3 genes methylated' HR = 0.83, 95% CI:0.61-1.15; '4-7 genes methylated' HR = 0.72, 95% CI:0.49-1.04). No associations were observed with respect to the Economic Depression and WWII years.
This is the first study indicating that exposure to a severe, transient environmental condition during adolescence and young adulthood may result in persistent epigenetic changes that later influence CRC development.
儿童和青少年时期的能量限制与结直肠癌（CRC）发病风险降低有关。在生长发育的这个关键时期，表观遗传失调可能是解释这些观察结果的一种机制。在荷兰饮食与癌症队列研究中，我们研究了早期生活能量限制与随后 CRC 风险之间的关系，该 CRC 的特征是（启动子）CpG 岛甲基化表型（CIMP）。
方法/主要发现：通过基线问卷（n=120856）收集饮食和危险因素信息。评估了三种暴露指标：饥饿冬季（1944-45 年）和二战期间（1940-44 年）的居住地，以及经济大萧条（1932-40 年）期间父亲的就业状况。对石蜡包埋肿瘤组织中的 DNA 进行甲基化特异性 PCR（MSP），根据 Weisenberger 标志物确定 CIMP 状态。随访 7.3 年后，603 例和 4631 例亚组成员可用于分析。Cox 回归用于计算根据三个能量限制时间段，根据年龄和性别调整后，CIMP+（27.7%）和 CIMP-（72.3%）肿瘤的风险比（HR）和 95%置信区间。与未暴露于饥饿冬季的个体相比，饥饿冬季期间暴露于严重饥荒的个体患 CIMP 特征肿瘤的风险降低（HR0.65，95%CI：0.45-0.92）。进一步将个体按启动子区域中“0-1”“2-3”或“4-7”个基因甲基化的指数进行分类，表明暴露于饥饿冬季与启动子过度甲基化的程度有关（“0-1 个基因甲基化”HR=1.01，95%CI：0.74-1.37；“2-3 个基因甲基化”HR=0.83，95%CI：0.61-1.15；“4-7 个基因甲基化”HR=0.72，95%CI：0.49-1.04）。与经济大萧条和二战期间没有关联。
这是第一项表明，青春期和成年早期暴露于严重的、短暂的环境条件下，可能导致持续的表观遗传变化，进而影响 CRC 的发展。
