Alterations to DNA methylation patterns induced by chemotherapy treatment are associated with negative impacts on the olfactory pathway.

IF 6.1 1区 医学 Q1 ONCOLOGY Breast Cancer Research Pub Date : 2023-11-06 DOI:10.1186/s13058-023-01730-4
Peh Joo Ho, Alexis Jiaying Khng, Benita Kiat-Tee Tan, Geok Hoon Lim, Su-Ming Tan, Veronique Kiak Mien Tan, Ryan Shea Ying Cong Tan, Elaine Hsuen Lim, Philip Tsau-Choong Iau, Ying Jia Chew, Yi Ying Lim, Mikael Hartman, Ern Yu Tan, Jingmei Li
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Abstract

Background: Exposure to cytotoxic chemotherapy treatment may alter DNA methylation (DNAm) in breast cancer patients.

Methods: We performed DNAm analysis in 125 breast cancer patients with blood drawn before and after chemotherapy, using the Illumina MethylationEPIC array. DNAm changes of 588,798 individual CpGs (including 41,207 promoter regions) were evaluated using linear regression models adjusted for monocyte proportion. Gene set enrichment analyses (GSEA) were conducted to identify key Gene Ontology (GO) biological processes or Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with chemotherapy. Results were validated in a separate cohort of breast cancer patients who were treated (n = 1273) and not treated (n = 872) by chemotherapy (1808 blood, 337 saliva).

Results: A total of 141 differentially methylated CpGs and 11 promoters were significantly associated with chemotherapy after multiple testing corrections in both the paired sample and single time point analyses. GSEA of promoter regions (pre-ranked by test statistics) identified six suppressed biological processes (p < 4.67e-8) related to sensory perception and detection of chemical stimuli, including smell perception (GO:0007606, GO:0007608, GO:0009593, GO:0050906, GO:0050907, and GO:0050911). The same six biological processes were significantly suppressed in the validation dataset (p < 9.02e-14). The KEGG pathway olfactory transduction (hsa04740) was also found to be significantly suppressed (ppaired-samples = 1.72e-9, psingle-timepoint-blood = 2.03e-15 and psingle-timepoint-saliva = 7.52e-56).

Conclusion: The enrichment of imprinted genes within biological processes and pathways suggests a biological mechanism by which chemotherapy could affect the perception of smell.

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化疗引起的DNA甲基化模式的改变与嗅觉通路的负面影响有关。
背景:暴露于细胞毒性化疗可能改变癌症患者的DNA甲基化(DNAm)。方法:采用Illumina MethylationEPIC阵列,对125例癌症患者化疗前后进行DNA分析。使用经单核细胞比例调整的线性回归模型评估588798个CpG个体(包括41207个启动子区)的DNAm变化。进行基因集富集分析(GSEA)以确定与化疗相关的关键基因本体论(GO)生物学过程或京都基因和基因组百科全书(KEGG)途径。结果在接受治疗的癌症患者的单独队列中得到验证(n = 1273)和未处理(n = 872)通过化疗(1808份血液,337份唾液)。结果:在配对样本和单时间点分析中,经过多次测试校正,共有141个差异甲基化CpG和11个启动子与化疗显著相关。启动子区的GSEA(通过测试统计进行预排序)确定了六个被抑制的生物过程(p 成对样本 = 1.72e-9,p单个时间点血液 = 2.03e-15和单个时间点唾液 = 7.52e-56)。结论:印迹基因在生物学过程和途径中的富集表明了化疗可能影响嗅觉的生物学机制。
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来源期刊
Breast Cancer Research
Breast Cancer Research 医学-肿瘤学
自引率
0.00%
发文量
76
期刊介绍: Breast Cancer Research is an international, peer-reviewed online journal, publishing original research, reviews, editorials and reports. Open access research articles of exceptional interest are published in all areas of biology and medicine relevant to breast cancer, including normal mammary gland biology, with special emphasis on the genetic, biochemical, and cellular basis of breast cancer. In addition to basic research, the journal publishes preclinical, translational and clinical studies with a biological basis, including Phase I and Phase II trials.
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