Kitahama Keiichiro, Ho Yu-Jui, Satomi Kaishi, Shibayama Takahiro, Nagahama Kiyotaka, Ohtsuka Kouki, Ohnishi Hiroaki, Sakamoto Yoshihiro, Shibahara Junji, Hayashi Akimasa
Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Sci Rep. 2025 Aug 6;15(1):28747. doi: 10.1038/s41598-025-13919-y.
Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis. We investigated intratumoral deoxyribonucleic acid methylation heterogeneity by analyzing 44 tumor samples and 5 normal samples from 6 cases of PDAC by using high-resolution methylation arrays. Two distinct methylation profiles were identified: T1, which is similar to normal pancreatic tissue and is associated with well-differentiated histology, and T2, which is significantly different from normal tissue and is linked to poorly differentiated morphology and squamous features. Validation using The Cancer Genome Atlas (TCGA) confirmed these profiles and revealed the association of T2 with shorter disease-free survival (p = 0.04). Differentially methylated region analysis identified the substantial hypomethylation of transcription regulation genes in T2 profiles (false discovery rate [FDR] q < 0.001). Gene set enrichment analysis with TCGA gene expression data demonstrated the upregulation of DNA repair and MYC target genes in T2 samples (FDR q < 0.001). Phylogenetic analysis with our multi-sampling dataset suggested an evolutionary trajectory from T1 to T2 profiles coinciding with aggressive phenotypes and increased genomic instability. Cases exhibited varying degrees of intratumoral heterogeneity from distinctly separated clusters to minimal differences. This comprehensive characterization of the epigenetic landscape of PDAC provides insights into tumor evolution and heterogeneity with potential implications for patient stratification and the development of epigenetic-based diagnostic and therapeutic strategies.
胰腺导管腺癌（PDAC）仍然是一种预后较差的致命性恶性肿瘤。我们通过使用高分辨率甲基化阵列分析6例PDAC患者的44个肿瘤样本和5个正常样本，研究了肿瘤内脱氧核糖核酸甲基化的异质性。鉴定出两种不同的甲基化谱：T1，类似于正常胰腺组织，与高分化组织学相关；T2，与正常组织有显著差异，与低分化形态和鳞状特征相关。使用癌症基因组图谱（TCGA）进行的验证证实了这些谱，并揭示了T2与较短无病生存期的关联（p = 0.04）。差异甲基化区域分析确定了T2谱中转录调控基因的大量低甲基化（错误发现率[FDR] q < 0.001）。利用TCGA基因表达数据进行的基因集富集分析表明，T2样本中DNA修复和MYC靶基因上调（FDR q < 0.001）。对我们的多样本数据集进行的系统发育分析表明，从T1到T2谱的进化轨迹与侵袭性表型和基因组不稳定性增加相吻合。病例表现出不同程度的肿瘤内异质性，从明显分离的簇到最小差异。对PDAC表观遗传景观的这种全面表征为肿瘤进化和异质性提供了见解，对患者分层以及基于表观遗传学的诊断和治疗策略的开发具有潜在意义。
