McCullough Lauren E, Chen Jia, Cho Yoon Hee, Khankari Nikhil K, Bradshaw Patrick T, White Alexandra J, Teitelbaum Susan L, Terry Mary Beth, Neugut Alfred I, Hibshoosh Hanina, Santella Regina M, Gammon Marilie D
Department of Epidemiology, Emory University, Atlanta, GA, 30322, USA.
Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
Breast Cancer Res. 2017 Feb 21;19(1):19. doi: 10.1186/s13058-017-0811-z.
Mechanisms underlying the inverse association between physical activity and survival after breast cancer are unresolved, but DNA methylation may play a role. We hypothesized that promoter methylation of breast cancer-related genes, as well as global methylation, may modify the association between prediagnostic recreational physical activity (RPA) and breast cancer mortality.
Using a population-based sample of 1254 women diagnosed with first primary breast cancer, we examined modification of the RPA-mortality association by gene-specific promoter methylation and global methylation. Average lifetime RPA was assessed from menarche to diagnosis through structured in-home interviews. Promoter methylation of 13 breast cancer-related genes was evaluated in archived tumor by methylation-specific polymerase chain reaction and MethyLight assay. Global methylation in white blood cell DNA was determined at long interspersed nucleotide element 1 and by the luminometric methylation assay. After approximately 15 years of follow-up, 486 patients had died, and 186 of the deaths were breast cancer-related. We used Cox proportional hazards regression to estimate HRs and 95% CIs as well as likelihood ratio tests to assess multiplicative interactions.
All-cause mortality was lower only among physically active women with methylated promoter of APC (HR 0.60, 95% CI 0.40-0.80), CCND2 (HR 0.56, 95% CI 0.32-0.99), HIN (HR 0.55, 95% CI 0.38-0.80), and TWIST1 (HR 0.28, 95% CI 0.14-0.56) in tumors, but not among those with unmethylated tumors (significant interaction p < 0.05). We found no interaction between RPA and global methylation.
The improved survival after breast cancer that is associated with RPA may be more pronounced in women with promoter tumor methylation in biologically plausible genes.
体育活动与乳腺癌患者生存率之间呈负相关的潜在机制尚未明确，但DNA甲基化可能发挥作用。我们推测，乳腺癌相关基因的启动子甲基化以及整体甲基化可能会改变诊断前休闲体育活动（RPA）与乳腺癌死亡率之间的关联。
我们以1254名被诊断为原发性乳腺癌的女性为基于人群的样本，通过基因特异性启动子甲基化和整体甲基化来研究RPA与死亡率关联的修饰情况。通过结构化的家庭访谈，从初潮到诊断评估平均终生RPA。通过甲基化特异性聚合酶链反应和MethyLight分析，在存档肿瘤中评估13个乳腺癌相关基因的启动子甲基化。通过长散在核苷酸元件1和荧光定量甲基化分析测定白细胞DNA中的整体甲基化。经过约15年的随访，486名患者死亡，其中186例死亡与乳腺癌相关。我们使用Cox比例风险回归来估计风险比（HR）和95%置信区间（CI），并使用似然比检验来评估相乘交互作用。
仅在肿瘤中APC、CCND2、HIN和TWIST1启动子甲基化的体力活动女性中，全因死亡率较低（HR分别为0.60、95%CI为0.40 - 0.80；HR为0.56、95%CI为0.32 - 0.99；HR为0.55、95%CI为0.38 - 0.80；HR为0.28、95%CI为0.14 - 0.56），而在肿瘤未甲基化的女性中则不然（显著交互作用p < 0.05）。我们未发现RPA与整体甲基化之间存在交互作用。
与RPA相关的乳腺癌患者生存率提高，在生物学上合理的基因中启动子肿瘤甲基化的女性中可能更为明显。
