Lung cancer is one of the most prevalent malignancies and is the most frequent cause of cancer-related death worldwide [1], [2]. Lung adenocarcinoma (LUAD), the most common pathological type, accounts for approximately 40% of all lung cancer cases [3]. Although the past decades have witnessed the clinical introduction of iconography, which distinctly promoted early diagnosis and prognosis evaluation of LUAD, specific biomarkers remain scarce because of the heterogeneity of LUAD. Genetic alterations, epigenetic changes, and environmental factors contribute to the formation and progression of LUAD. Epigenetic differences, such as histone modification and DNA methylation, have been considered critical factors in the tumorigenicity and heterogeneity of LUAD.

In histones, H3 lysine and arginine residues are the most ordinary acceptor sites of methylation markers. The specific residues that are modified, the degree and pattern of methylation, and the genomic context in which methylation occurs attributes to the different effects on gene activity [4]. Histone lysine methylation is a dynamic enzymatic process that can exist in one of three situations: mono-, di-, or tri-methylation. It is orchestrated by demethylases (KDMs) and methyltransferases (KMTs) that influence numerous biological processes, such as DNA replication, transcription, and chromosome maintenance. Generally, heterochromatin, exhibiting silent transcriptional activity in the human genome, is characterized by high levels of Histone 3 lysine 9 (H3K9) and Histone 3 lysine 27 methylation (H3K27) [5]. Abundant evidence has shown that H3K9 and H3K27 methylation are closely associated with different tumor progression and may act as potential epigenetic biomarkers for clinical assessment [6], [7]. SETDB1, which catalyzes H3K9 tri-methylation (H3K9me3), was confirmed to be a diagnostic biomarker and/or a potential therapeutic target in non-small cell lung cancer (NSCLC) [8], [9]. Enhancer of zeste homolog 2 (EZH2), in the context of polycomb repressive complex2 (PRC2), is a well-known methyltransferase that catalyzes H3K27me3 and elicits gene silencing [10]. Moreover, multivariate survival analysis showed that EZH2 high expression was associated with a poor outcome [11]. Further evidence suggest that compared with other factors, histone modification is the only independent factor affecting prognosis and can be used as a potential clinical marker [12], [13].

The importance of molecular pathology is increasing with the expansion of lung cancer research, particularly in the molecular discipline. However, the relationship between histone modification and pathological histology of LUAD remains unclear. The 2015 WHO classification adopted a new systematization for primary lung adenocarcinoma and described five distinct histologic subtypes: lepidic, papillary, acinar, micropapillary, and solid. The prognostic significance of dominated histologic subtyping in lung adenocarcinoma has been evaluated in many absolute researches, and the micropapillary subtype has been confirmed to be related to the aggressive clinical biological behavior. The filigree pattern is a novel morphological pattern which was introduced by Emoto et al. from the Memorial Sloan Kettering Cancer Center, indicating that the filigree pattern was with the classical MP pattern [14]. Similar clinical features and survival outcomes were observed between the filigree pattern and the classical MP pattern, indicating that the two patterns were frequently associated. In this scientific research, we improved our understanding of the epigenetic system involved in tumor-suppressor gene degradation by evaluating H3K9 and H3K27 levels. The purpose of our scientific research is to enrich the expression spectrum and clinical value of histone methylation markers in LUAD.