|
对于临床医生而言，一个永不休止的灵魂拷问就是：赵女士、钱小姐、孙阿姨、李阿婆、隔壁老王……患了同样的病，用了同样的药，为什么效果不一样？其实，除了外部原因，还有内部原因；除了药物原因，还有遗传原因；除了先天遗传原因，还有后天遗传原因…… 关于阿司匹林用药史与乳腺癌所致死亡风险，既往研究结果众说纷纭、莫衷一是、存在分歧。某些学者推测，除了经典遗传变化（例如基因突变），基因甲基化等与基因排列顺序无关的表观遗传变化，或许有助于明确阿司匹林用药史与乳腺癌生存结局的潜在生物学机制。 2019年8月12日，美国癌症学会《癌症》在线发表北卡罗来纳大学教堂山分校、亚特兰大埃默里大学、美国环境健康科学研究所、加利福尼亚大学伯克利分校、罗氏全球药品开发上海中心、蒙大拿大学、纽约哥伦比亚大学、纽约西奈山伊坎医学院的流行病学研究报告，首次分析了乳腺癌相关基因甲基化整体水平和（或）启动子甲基化与阿司匹林用药史对乳腺癌所致死亡风险的影响。 该研究通过面对面访谈，对1996年8月1日～1997年7月31日参加纽约长岛乳腺癌研究项目的1508例首次诊断原发乳腺癌女性人群诊断前阿司匹林用药情况进行定量分析。通过细胞核较长散在重复序列-1（LINE-1）和发光甲基化测定法，对外周血液甲基化整体水平进行测定。通过甲基化特异聚合酶链反应和甲基化荧光测定法，对13种乳腺癌相关基因启动子甲基化进行测定。根据全国死亡指数截至2014年12月31日的数据，确定生存状态。通过多因素比例风险回归模型分析，推算死亡风险比和95%置信区间，并且通过似然比检验，对多重相互作用进行评估。 结果，1266例女性完成甲基化测定并且阿司匹林用药数据完整，其中全部原因所致死亡476例、乳腺癌所致死亡202例。 阿司匹林用药者与从未用药者相比，全部原因所致死亡风险：
阿司匹林用药者与从未用药者相比，乳腺癌所致死亡风险：
因此，该研究结果表明，乳腺癌LINE-1LINE-1甲基化整体水平、BRCA1和PR基因启动子甲基化可能与阿司匹林用药史相互作用，对乳腺癌诊断后死亡风险产生影响。 对此，麦迪逊威斯康星大学发表同期社论：表观遗传与阿司匹林对乳腺癌生存的不同影响——了解人类乳腺癌易感性与风险的机会。对于临床研究和人群健康研究，一个永不休止的问题就是：人类对治疗的效果如何，以及为何不同。纽约长岛乳腺癌研究项目二次分析结果表明，阿司匹林用药史与乳腺癌所致死亡风险之间的相关性可能取决于患者基因甲基化特征，或将有助于根据基因甲基化特征，确定哪些女性可以对阿司匹林获益，以改善其乳腺癌诊断后的生存。探索表观遗传与阿司匹林等低成本疗法之间的相互作用，对推进人群健康科学和生物医学研究具有重要意义。 Cancer. 2019 Aug 12. [Epub ahead of print] Prediagnosis aspirin use, DNA methylation, and mortality after breast cancer: A population-based study. Wang T, McCullough LE, White AJ, Bradshaw PT, Xu X, Cho YH, Terry MB, Teitelbaum SL, Neugut AI, Santella RM, Chen J, Gammon MD. University of North Carolina, Chapel Hill, North Carolina; Emory University, Atlanta, Georgia; National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; University of California, Berkeley, California; Roche Product Development in Asia-Pacific, Shanghai, China; University of Montana, Missoula, Montana; Columbia University, New York, New York; Icahn School of Medicine at Mount Sinai, New York, New York. Findings from this study suggest that the association between aspirin use and mortality after breast cancer may depend upon patients' DNA methylation profiles. The study may help to identify women who may benefit from aspirin use to improve survival after a breast cancer diagnosis because of their DNA methylation profile. BACKGROUND: The authors hypothesized that epigenetic changes may help to clarify the underlying biologic mechanism linking aspirin use to breast cancer prognosis. To the authors' knowledge, this is the first epidemiologic study to examine whether global methylation and/or tumor promoter methylation of breast cancer-related genes interact with aspirin use to impact mortality after breast cancer. METHODS: Prediagnosis aspirin use was assessed through in-person interviews within a population-based cohort of 1508 women diagnosed with a first primary breast cancer in 1996 and 1997. Global methylation in peripheral blood was assessed by long interspersed elements-1 (LINE-1) and the luminometric methylation assay. Promoter methylation of 13 breast cancer-related genes was measured in tumor by methylation-specific polymerase chain reaction and the MethyLight assay. Vital status was determined by the National Death Index through December 31, 2014 (N = 202/476 breast cancer-specific/all-cause deaths identified among 1266 women with any methylation assessment and complete aspirin data). Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs, and the likelihood ratio test was used to evaluate multiplicative interactions. RESULTS: All-cause mortality was elevated among aspirin users who had methylated promotor of BRCA1 (HR, 1.67; 95% CI, 1.26-2.22), but not among those with unmethylated promoter of BRCA1 (HR, 0.99; 95% CI, 0.67-1.45; P for interaction ≤.05). Decreased breast cancer-specific mortality was observed among aspirin users who had unmethylated promotor of BRCA1 and PR and global hypermethylation of LINE-1 (HR, 0.60, 0.78, and 0.63, respectively; P for interaction ≤.05), although the 95% CIs included the null. CONCLUSIONS: The current study suggests that the LINE-1 global methylation and promoter methylation of BRCA1 and PR in tumor may interact with aspirin use to influence mortality after breast cancer. KEYWORDS: aspirin; breast cancer; DNA methylation; epigenetic; mortality DOI: 10.1002/cncr.32364 Cancer. 2019 Aug 12. [Epub ahead of print] Epigenetics and differential effects of aspirin on breast cancer survival: Opportunities for understanding human susceptibility and risk. Malecki KM. University of Wisconsin Madison, Madison, Wisconsin. An unending question in clinical and population health research is how and why the human response to treatment varies. Collective findings from the Long Island Breast Cancer Study Project provide further evidence that research examining interactions between epigenetics and low-cost therapies such as aspirin are important in advancing population health science and biomedical research. KEYWORDS: aspirin; breast cancer; DNA methylation; epigenetic; mortality DOI: 10.1002/cncr.32365
|
|
|
