Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance
Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance
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DOI：
10.1073/pnas.0503218102
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发表时间：
2005-06-14
影响因子：
11.1
通讯作者：
Walker, CL
中科院分区：
文献类型：
--
作者：
Cook, JD;Davis, BJ;Walker, CL
基因-环境相互作用是癌症风险的重要决定因素。传统上，基因-环境相互作用被认为通过促进或抑制肿瘤发生所需的额外体细胞突变的获得来促进肿瘤抑制基因的突变。在这里，我们证明了一种独特的类型的基因-环境相互作用可以发生在发展过程中，以提高肿瘤抑制基因缺陷在成人的发病率。我们使用在易患子宫平滑肌瘤的结节性硬化症复合体2（Tsc-2）肿瘤抑制基因中携带生殖系缺陷的大鼠，发现在子宫发育过程中早期暴露于己烯雌酚使肿瘤抑制基因突变率从65%增加到> 90%，并使遗传易感动物的肿瘤多样性和大小增加，但在野生型大鼠中未能诱导肿瘤。这种暴露被证明会在发育中的子宫肌层上产生激素印记，导致肿瘤发生前雌激素反应基因的表达增加。正常Tsc-2等位基因的功能丧失仍然是肿瘤发生的限速事件;然而，相对于未暴露动物中发生的肿瘤，暴露动物中发生的肿瘤显示出对类固醇激素的增殖反应增强。这些数据表明，在发育过程中暴露于环境因素可以永久性地重新编程正常的生理组织反应，从而导致遗传易感个体的肿瘤抑制基因突变率增加。
Gene-environment interactions are important determinants of cancer risk. Traditionally, gene-environment interactions are thought to contribute to tumor-suppressor-gene penetrance by facilitating or inhibiting the acquisition of additional somatic mutations required for tumorigenesis. Here, we demonstrate that a distinctive type of gene-environment interaction can occur during development to enhance the penetrance of a tumor-suppressor-gene defect in the adult. Using rats carrying a germ-line defect in the tuberous sclerosis complex 2 (Tsc-2) tumor-suppressor gene predisposed to uterine leiomyomas, we show that an early-life exposure to diethylstilbestrol during development of the uterus increased tumor-suppressor-gene penetrance from 65% to > 90% and tumor multiplicity and size in genetically predisposed animals, but it failed to induce tumors in wild-type rats. This exposure was shown to impart a hormonal imprint on the developing uterine myometrium, causing an increase in expression of estrogen-responsive genes before the onset of tumors. Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals. These data suggest that exposure to environmental factors during development can permanently reprogram normal physiological tissue responses and thus lead to increased tumor-suppressor-gene penetrance in genetically susceptible individuals.