Shijimaya Takuya, Tahara Tomomitsu, Yamazaki Jumpei, Kobayashi Sanshiro, Matsumoto Yasushi, Nakamura Naohiro, Takahashi Yu, Tomiyama Takashi, Fukui Toshiro, Shibata Tomoyuki, Naganuma Makoto
Third Department of Internal Medicine, Kansai Medical University, 2-5-1 Shin-Machi, Hirakata, Osaka, 573-1010, Japan.
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Clin Epigenetics. 2024 Dec 19;16(1):184. doi: 10.1186/s13148-024-01801-z.
Interaction between host genotoxic changes and mucosa-associated microbiome (MAM) dysbiosis may have a role in various digestive cancers. We investigated MAM in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) progression sequence and its association with host genotoxic changes. 16S rRNA gene sequencing was performed in three different groups of biopsies from nonneoplastic BE from patients without cancer (N, normal group; n = 47) and with EAC (ADJ, adjacent group; n = 27). Endoscopic biopsies were also obtained from EAC tissues (T, tumor group; n = 22). Results were correlated with TP53 mutation, telomere length and DNA methylation of candidate genes (N33, DPYS, SLC16A12, miR124A3 and miR34bc). Genome-wide DNA methylation examined by reduced representation bisulfite sequencing (RRBS) was available for 32 samples (n = 12 for N, n = 12 for ADJ and n = 22 for T groups). Lower microbial alpha diversity measures were observed in ADJ/T groups relative to N group and associated with higher mean Z score DNA methylation of candidate genes. Specific genera (n = 16) with significant change between ADJ/T groups relative to N group occurred mostly in ADJ group (13/16) and half of them (8/16) were associated with DNA methylation status. Integrated MAM and genome-wide methylation analysis demonstrated that hyper-methylated sites, associated with lower alpha diversity measures dominantly occurred within near the transcription start site, codifying genes were involved in metabolic processes. Our result shows that microbial dysbiosis in EAC mostly occurs in adjacent BE and such dysbiosis was associated with DNA methylation status, offering support for a pathogenic role of interaction between host genotoxic changes and MAM in this tumor type.
宿主基因毒性变化与黏膜相关微生物群（MAM）失调之间的相互作用可能在各种消化系统癌症中发挥作用。我们研究了巴雷特食管（BE）和食管腺癌（EAC）进展序列中的MAM及其与宿主基因毒性变化的关联。对来自无癌患者的非肿瘤性BE（N，正常组；n = 47）和患有EAC患者的三组不同活检样本进行了16S rRNA基因测序（ADJ，相邻组；n = 27）。还从EAC组织（T，肿瘤组；n = 22）获取了内镜活检样本。结果与TP53突变、端粒长度以及候选基因（N33、DPYS、SLC16A12、miR124A3和miR34bc）的DNA甲基化相关。通过简化代表性亚硫酸氢盐测序（RRBS）检测的全基因组DNA甲基化数据可用于32个样本（N组n = 12，ADJ组n = 12，T组n = 22）。相对于N组，ADJ/T组中观察到较低的微生物α多样性指标，且与候选基因的较高平均Z评分DNA甲基化相关。相对于N组，ADJ/T组之间有显著变化的特定属（n = 16）大多出现在ADJ组（13/16），其中一半（8/16）与DNA甲基化状态相关。综合MAM和全基因组甲基化分析表明，与较低α多样性指标相关的高甲基化位点主要出现在转录起始位点附近，编码基因参与代谢过程。我们的结果表明，EAC中的微生物失调主要发生在相邻的BE中，这种失调与DNA甲基化状态相关，为宿主基因毒性变化与MAM之间的相互作用在这种肿瘤类型中的致病作用提供了支持。
