Dataset Information

DNA methylation-based lung adenocarcinoma subtypes can predict prognosis, recurrence, and immunotherapeutic implications.

ABSTRACT: The marked heterogeneity of lung adenocarcinoma (LUAD) makes its diagnosis and treatment difficult. In addition, the aberrant DNA methylation profile contributes to tumor heterogeneity and alters the immune response. We used DNA methylation array data from publicly available databases to establish a predictive model for LUAD prognosis. Thirty-three methylation sites were identified as specific prognostic biomarkers, independent of patients' clinical characteristics. These methylation profiles were used to identify potential drug candidates and study the immune microenvironment of LUAD and response to immunotherapy. When compared with the high-risk group, the low-risk group had a lower recurrence rate and favorable prognosis. The tumor microenvironment differed between the two groups as reflected by the higher number of resting dendritic cells and a lower number of monocytes and resting mast cells in the low-risk group. Moreover, low-risk patients reported higher immune and stromal scores, lower tumor purity, and higher expression of HLA genes. Low-risk patients responded well to immunotherapy due to higher expression of immune checkpoint molecules and lower stemness index. Thus, our model predicted a favorable prognosis and increased overall survival for patients in the low-risk methylation group. Further, this model could provide potential drug targets to develop effective immunotherapies for LUAD.

SUBMITTER: Xu F

PROVIDER: S-EPMC7803536 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

DNA methylation-based lung adenocarcinoma subtypes can predict prognosis, recurrence, and immunotherapeutic implications.

Xu Feng F He Lulu L Zhan Xueqin X Chen Jiexin J Xu Huan H Huang Xiaoling X Li Yangyi Y Zheng Xiaohe X Lin Ling L Chen Yongsong Y

Aging 20201121 24

The marked heterogeneity of lung adenocarcinoma (LUAD) makes its diagnosis and treatment difficult. In addition, the aberrant DNA methylation profile contributes to tumor heterogeneity and alters the immune response. We used DNA methylation array data from publicly available databases to establish a predictive model for LUAD prognosis. Thirty-three methylation sites were identified as specific prognostic biomarkers, independent of patients' clinical characteristics. These methylation profiles we ...[more]

PMID: 33234739

Similar Datasets

Project description:The aim of this study was to clarify the significance of DNA methylation alterations at precancerous stages of lung adenocarcinoma. Using single-CpG resolution Infinium array, genome-wide DNA methylation analysis was performed in 36 samples of normal lung tissue obtained from patients without any primary lung tumor, 145 samples of non-cancerous lung tissue (N) obtained from patients with lung adenocarcinomas, and 145 samples of tumorous tissue (T). Stepwise progression of DNA methylation alterations from normal lung tissue to non-cancerous lung tissue obtained from patients with lung adenocarcinomas, and then tumorous tissue samples, was observed at 3,270 CpG sites, suggesting that non-cancerous lung tissue obtained from patients with lung adenocarcinomas was at precancerous stages with DNA methylation alterations. At CpG sites of 2,083 genes, DNA methylation status in samples of non-cancerous lung tissue obtained from patients with lung adenocarcinomas was significantly correlated with recurrence after establishment of lung adenocarcinomas. Among such recurrence-related genes, 28 genes are normally unmethylated (average ?-values based on Infinium assay in normal lung tissue samples was less than 0.2) and their DNA hypermethylation at precancerous stages was strengthened during progression to lung adenocarcinomas (??(T-N)>0.1). Among these 28 genes, we focused on 6 for which implications in transcription regulation, apoptosis or cell adhesion had been reported. DNA hypermethylation of the ADCY5, EVX1, GFRA1, PDE9A, and TBX20 genes resulted in reduced mRNA expression in tumorous tissue samples. 5-Aza-2'-deoxycytidine treatment of lung cancer cell lines restored the mRNA expression levels of these 5 genes. Reduced mRNA expression in tumorous tissue samples was significantly correlated with tumor aggressiveness. These data suggest that DNA methylation alterations at precancerous stages determine tumor aggressiveness and outcome through silencing of specific genes.

Project description:BackgroundLung cancer is the leading cause of cancer morbidity and mortality worldwide, however, the individualized treatment is still unsatisfactory. DNA methylation can affect gene regulation and may be one of the most valuable biomarkers in predicting the prognosis of lung adenocarcinoma. This study was aimed to identify methylation CpG sites that may be used to predict lung adenocarcinoma prognosis.MethodsThe Cancer Genome Atlas (TCGA) database was used to detect methylation CpG sites associated with lung adenocarcinoma prognosis and construct a methylation signature model. Then, a Chinese cohort was carried out to estimate the association between methylation and lung adenocarcinoma prognosis. Biological function studies, including demethylation treatment, cell proliferative capacity, and gene expression changes in lung adenocarcinoma cell lines, were further performed.ResultsIn the TCGA set, three methylation CpG sites were selected that were associated with lung adenocarcinoma prognosis (cg14517217, cg15386964, and cg18878992). The risk of mortality was increased in lung adenocarcinoma patients with the gradual increase level of methylation signature based on three methylation sites levels (HR = 45.30, 95% CI = 26.69-66.83; p < 0.001). The C-statistic value increased to 0.77 when age, gender, and other clinical variables were added to the signature to prediction model. A similar situation was confirmed in Chinese lung adenocarcinoma cohort. In the biological function studies, the proliferative capacity of cell lines was inhibited when the cells were demethylated with 5-aza-2'-deoxycytidine (5-aza-2dC). The mRNA and protein expression levels of SEPT9 and HIST1H2BH (cg14517217 and cg15386964) were downregulated with different concentrations of 5-aza-2dC treatment, while cg18878992 showed the opposite result.ConclusionThis study is the first to develop a three-CpG-based model for lung adenocarcinoma, which is a practical and useful tool for prognostic prediction that has been validated in a Chinese population.

Project description:BackgroundThe role of tumor-infiltrating B-cells (TIBs) and intratumorally-produced antibodies in cancer-immunity interactions essentially remains terra incognita. In particular, it remains unexplored how driver mutations could be associated with distinct TIBs signatures and their role in tumor microenvironment.MethodsHere we analyzed associations of immunoglobulin isotypes and clonality with survival in TCGA RNA-Seq data for lung adenocarcinoma (LUAD), stratifying patients into 12 driver mutation and phenotypic tumor subgroups.ResultsWe revealed several unexpected associations between TIBs behavior and prognosis. Abundance and high proportion of IgG1 isotype, and low proportion of IgA among all intratumorally produced immunoglobulins were specifically associated with improved overall survival for KRASmut but not KRASwt LUAD, revealing the first link between a driver mutation and B-cell response. We found specific IgG1 signature associated with long survival, which suggests that particular specificities of IgG1+ TIBs could be beneficial in KRASmut LUAD. In contrast to our previous observations for melanoma, highly clonal IgG1 production by plasma cells had no meaningful effect on prognosis, suggesting that IgG1+ TIBs may exert a beneficial effect in KRASmut cases in an alternative way, such as efficient presentation of cognate antigens or direct B cell attack on tumor cells. Notably, a high proportion of the IgG1 isotype is positively correlated with the non-silent mutation burden both in the general LUAD cohort and in most patient subgroups, supporting a role for IgG1+ TIBs in antigen presentation. Complementing the recent finding that the presence of stromal IgG4-producing cells is associated with a favorable prognosis for patients with stage I squamous cell carcinoma, we show that the abundance of IgG4-producing TIBs likewise has a strong positive effect on overall survival in STK11mut and proximal proliferative subgroups of LUAD patients. We hypothesize that the positive role of IgG4 antibodies in some of the lung cancer subtypes could be associated with reported inability of IgG4 isotype to form immune complexes, thus preventing immunosuppression via activation of the myeloid-derived suppressor cell (MDSC) phenotype.ConclusionsWe discover prominent and distinct associations between TIBs antibody isotypes and survival in lung adenocarcinoma carrying specific driver mutations. These findings indicate that particular types of tumor-immunity relations could be beneficial in particular driver mutation context, which should be taken into account in developing strategies of cancer immunotherapy and combination therapies. Specificity of protective B cell populations in specific cancer subgroups could become a clue to efficient targeted immunotherapies for appropriate cohorts of patients.

Dataset Information

DNA methylation-based lung adenocarcinoma subtypes can predict prognosis, recurrence, and immunotherapeutic implications.

Publications

DNA methylation-based lung adenocarcinoma subtypes can predict prognosis, recurrence, and immunotherapeutic implications.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets