Association of frequent hypermethylation with high grade histological subtype in lung adenocarcinoma
Year: 2023
Type: article
Study design: Observational Study
Abstract: Lung adenocarcinoma is classified morphologically into five histological subtypes according to the WHO classification. While each histological subtype correlates with a distinct prognosis, the molecular basis has not been fully elucidated. Here we conducted DNA methylation analysis of 30 lung adenocarcinoma cases annotated with the predominant histological subtypes and three normal lung cases using the Infinium BeadChip. Unsupervised hierarchical clustering analysis revealed three subgroups with different methylation levels: high-, intermediate-, and low-methylation epigenotypes (HME, IME, and LME). Micropapillary pattern (MPP)-predominant cases and those with MPP components were significantly enriched in HME (p = 0.02 and p = 0.03, respectively). HME cases showed a significantly poor prognosis for recurrence-free survival (p < 0.001) and overall survival (p = 0.006). We identified 365 HME marker genes specifically hypermethylated in HME cases with enrichment of "cell morphogenesis" related genes; 305 IME marker genes hypermethylated in HME and IME, but not in LME, with enrichment "embryonic organ morphogenesis"-related genes; 257 Common marker genes hypermethylated commonly in all cancer cases, with enrichment of "regionalization"-related genes. We extracted surrogate markers for each epigenotype and designed pyrosequencing primers for five HME markers (TCERG1L, CXCL12, FAM181B, HOXA11, GAD2), three IME markers (TBX18, ZNF154, NWD2) and three Common markers (SCT, GJD2, BARHL2). DNA methylation profiling using Infinium data was validated by pyrosequencing, and HME cases defined by pyrosequencing results also showed the worse recurrence-free survival. In conclusion, lung adenocarcinomas are stratified into subtypes with distinct DNA methylation levels, and the high-methylation subtype correlated with MPP-predominant cases and those with MPP components and showed a poor prognosis.
Source: Cancer Science
DOI: 10.1111/cas.15817
Institutions: Chiba University, Chiba University Hospital
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,600
Awards: G1159675888, 環境がゲノムにもたらすエピゲノム修飾の理解に基づいた消化器癌本態解明とその領域特異的制御, Establishment of standard precision diagnosis methodology for lung cancer surgery using respiratory endoscopy technology., Alteration of epigenome in seletecd genomic regions against gastrointestinal cancer, Mechanism on epigenetic carcinogenesis of EB virus-gastric cancer focused on senescence, Elucidation of the nature and development of therapeutic strategies for sporadic MSI-positive tumors across organs, Elucidation of cancer mutagen by novel signature analysis
OpenAlex ID: W4366603440