Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.
Correlates of Prenatal and Early-Life Tobacco Smoke Exposure and Frequency of Common Gene Deletions in Childhood Acute Lymphoblastic Leukemia.
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DOI：
10.1158/0008-5472.can-16-2571
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发表时间：
2017-04-01
期刊：
影响因子：
11.2
通讯作者：
Wiemels JL
中科院分区：
文献类型：
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作者：
de Smith AJ;Kaur M;Gonseth S;Endicott A;Selvin S;Zhang L;Roy R;Shao X;Hansen HM;Kang AY;Walsh KM;Dahl GV;McKean-Cowdin R;Metayer C;Wiemels JL
接触烟草烟雾与儿童急性淋巴细胞白血病 (ALL) 的风险相关。了解烟草暴露与特定突变之间的关系可能会产生病因学见解。我们进行了仅病例分析，以探讨产前和生命早期的烟草烟雾暴露是否影响致白血病基因组缺失的形成。在加州儿童白血病研究的 559 个治疗前肿瘤样本中评估了 ALL 中经常缺失的 8 个基因（CDKN2A、ETV6、IKZF1、PAX5、RB1、BTG1、PAR1 区域和 EBF1）的体细胞拷贝数。使用访谈辅助问卷以及芳基烃受体阻遏物（AHRR）中的 DNA 甲基化来评估父母和儿童的被动烟草暴露，AHRR 是孕期母亲吸烟暴露的前哨表观遗传生物标志物。使用多变量泊松回归来测试吸烟暴露与缺失总数之间的关联。缺失负担因亚型而异，高超二倍体中的缺失频率较低，而 ETV6-RUNX1 融合 ALL 中的缺失频率较高。每个病例的缺失总数与烟草烟雾暴露呈正相关，特别是母亲曾经吸烟的情况（平均值比率，RM=1.31；95% CI：1.08–1.59）、母亲在怀孕期间吸烟（RM=1.48；95% CI：1.12–1.94）和母乳喂养期间（RM=2.11；95% CI：1.48–3.02）。与女性相比，男性儿童与母亲曾经吸烟的关联程度更强（Pinteraction=0.04）。缺失总数也与 AHRR 表观遗传生物标志物的 DNA 甲基化相关（RM=1.32；95% CI：1.02–1.69）。我们的研究结果表明，产前和生命早期接触烟草烟雾会增加罹患 ALL 的儿童体细胞缺失的频率。
Tobacco smoke exposure has been associated with risk of childhood acute lymphoblastic leukemia (ALL). Understanding the relationship between tobacco exposures and specific mutations may yield etiologic insights. We carried out a case-only analysis to explore whether prenatal and early-life tobacco smoke exposure influences the formation of leukemogenic genomic deletions. Somatic copy-number of 8 genes frequently deleted in ALL (CDKN2A, ETV6, IKZF1, PAX5, RB1, BTG1, PAR1 region, and EBF1) was assessed in 559 pre-treatment tumor samples from the California Childhood Leukemia Study. Parent and child passive tobacco exposure was assessed using interview-assisted questionnaires as well as DNA methylation in aryl-hydrocarbon receptor repressor (AHRR), a sentinel epigenetic biomarker of exposure to maternal smoking during pregnancy. Multivariable Poisson regressions were used to test association between the smoking exposures and total number of deletions. Deletion burden varied by subtype, with a lower frequency in high-hyperdiploid and higher frequency in ETV6-RUNX1 fusion ALL. Total number of deletions per case was positively associated with tobacco smoke exposure, in particular for maternal ever-smoking (ratio of means, RM=1.31; 95% CI: 1.08–1.59), maternal smoking during pregnancy (RM=1.48; 95% CI: 1.12–1.94), and during breastfeeding (RM=2.11; 95% CI: 1.48–3.02). The magnitude of association with maternal ever-smoking was stronger in male children compared with females (Pinteraction=0.04). Total number of deletions was also associated with DNA methylation at the AHRR epigenetic biomarker (RM=1.32; 95% CI: 1.02–1.69). Our results suggest that prenatal and early-life tobacco smoke exposure increase the frequency of somatic deletions in children who develop ALL.