Division of Human Biology, Fred Hutchinson Cancer Research Center, PO Box 19024, 1100 Fairview Ave N, Seattle, WA, 98109-1024, USA.
Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, PO Box 19024, Seattle, WA, 98109-1024, USA.
Genome Med. 2018 Feb 27;10(1):17. doi: 10.1186/s13073-018-0520-y.
Use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been shown to protect against tetraploidy, aneuploidy, and chromosomal alterations in the metaplastic condition Barrett's esophagus (BE) and to lower the incidence and mortality of esophageal adenocarcinoma (EA). The esophagus is exposed to both intrinsic and extrinsic mutagens resulting from gastric reflux, chronic inflammation, and exposure to environmental carcinogens such as those found in cigarettes. Here we test the hypothesis that NSAID use inhibits accumulation of point mutations/indels during somatic genomic evolution in BE.
Whole exome sequences were generated from 82 purified epithelial biopsies and paired blood samples from a cross-sectional study of 41 NSAID users and 41 non-users matched by sex, age, smoking, and continuous time using or not using NSAIDs.
NSAID use reduced overall frequency of point mutations across the spectrum of mutation types, lowered the frequency of mutations even when adjusted for both TP53 mutation and smoking status, and decreased the prevalence of clones with high variant allele frequency. Never smokers who consistently used NSAIDs had fewer point mutations in signature 17, which is commonly found in EA. NSAID users had, on average, a 50% reduction in functional gene mutations in nine cancer-associated pathways and also had less diversity in pathway mutational burden compared to non-users.
These results indicate NSAID use functions to limit overall mutations on which selection can act and supports a model in which specific mutant cell populations survive or expand better in the absence of NSAIDs.
阿司匹林和其他非甾体抗炎药 (NSAIDs) 的使用已被证明可预防多倍体、非整倍体和化生条件下的 Barrett 食管 (BE) 的染色体改变，并降低食管腺癌 (EA) 的发病率和死亡率。食管暴露于胃反流、慢性炎症和接触环境致癌物（如香烟中发现的致癌物）引起的内在和外在诱变剂。在这里，我们检验了 NSAID 使用抑制 BE 体细胞基因组进化过程中点突变/插入缺失积累的假设。
对来自 41 名 NSAID 使用者和 41 名非使用者的 82 个纯化上皮活检和配对血液样本进行了全外显子组测序，这些样本通过性别、年龄、吸烟和是否使用 NSAIDs 进行了匹配。
NSAID 使用降低了各种突变类型的点突变总体频率，即使在调整了 TP53 突变和吸烟状况后，突变频率也降低了，并且降低了具有高变异等位基因频率的克隆的流行率。从不吸烟者中，持续使用 NSAIDs 的人在 EA 中常见的 17 号特征中突变较少。与非使用者相比，NSAID 使用者在九个癌症相关途径中的功能性基因突变平均减少了 50%，并且途径突变负担的多样性也较少。
这些结果表明 NSAID 使用可限制选择可以作用的总体突变，并支持这样一种模型，即特定的突变细胞群在没有 NSAIDs 的情况下生存或更好地扩展。
