Investigation on the potential of circulating tumor DNA methylation patterns as prognostic biomarkers for lung squamous cell carcinoma

Liu, Yutao; Feng, Yu; Hou, Ting; Lizaso, Analyn; Xu, Feng; Xing, Puyuan; Wang, Hongyu; Kang, Qiaolin; Zhang, Lu; Shi, Yuankai; Hu, Xingsheng

doi:10.21037/tlcr-20-1070

Cited by 9 publications

(8 citation statements)

References 45 publications

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“…The whole-genome bisulfite sequencing library was generated by the brELSA method (Burning Rock Biotech, Guangzhou, China) ( 13 , 14 ). Briefly, purified cell-free DNA (cfDNA) was incubated with sodium bisulfite.…”

Section: Methodsmentioning

confidence: 99%

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Development and validation of a tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients

Yang¹,

Tang²,

Wang³

et al. 2022

Gland Surg

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Background: Pancreatic cancer (PC) is a highly malignant tumor associated with low survival rates. It is challenging to predict the survival of surgically resected patients with PC. A prognostic staging tool could be beneficial to guide treatments and also aid post-treatment surveillance. This study aimed to identify tissuebased DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients.Methods: We performed a monocentric, retrospective study that included 50 patients with stage I-II PC from The First Affiliated Hospital of Soochow University (SU cohort). Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted methylation profiling.Results: In total, 1,162 DNA methylation blocks (DMBs) were differentially methylated in tumor tissues compared with adjacent long-distance tissues (P<0.05). Least Absolute Shrinkage and Selection Operator (LASSO) and stepwise regression analyses revealed a significant correlation between the methylation signature (risk score) and overall survival (OS). Patients in the high-risk group showed significantly poorer OS than those in the low-risk group in the survival analysis [P≤0.001; area under curve (AUC) at 1 year, 0.789; AUC at 2 years, 0.852]. The risk score was also validated using clinical and methylation data of 166 PC patients from The Cancer Genome Atlas pancreatic ductal adenocarcinoma (TCGA-PDAC) dataset.Patients in the high-risk group showed significantly poorer OS than those in the low-risk group (P=0.004; AUC at 1 years, 0.677; AUC at 3 years, 0.611). When clinical parameters were considered, the risk score was the only independent prognostic parameter (P<0.001) in the Cox regression analysis. Furthermore, low-risk patients had higher levels of immune infiltration, anti-tumor immune activation, and increased sensitivity to gemcitabine and paclitaxel. In contrast, high-risk patients had lower KRAS mutation rates and benefited more from cisplatin.Conclusions: In our study, we constructed and validated a tissue-based DNA methylation risk-score model to predict prognosis and identify PC patients with a high mortality risk at the time of surgery. This model might provide a tissue-based prognostic assessment tool for clinicians to aid their treatment decision-making.

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Section: Methodsmentioning

confidence: 99%

“…Methylation levels were defined as scores to reflect the methylation features of each sample ( 13 , 14 ). The genomic region between the neighboring CpG sites with the r 2 value was defined as the methylation block.…”

Section: Methodsmentioning

confidence: 99%

Development and validation of a tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients

Yang¹,

Tang²,

Wang³

et al. 2022

Gland Surg

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“…Lung squamous cell carcinoma (LUSC), one of the major subtypes of NSCLC, accounts for nearly 30% of all confirmed cases of NSCLC, with the characteristics of rapid growth, quick metastasis and high mortality 2 . Although relatively sensitive to chemotherapy and radiotherapy, the 5-year survival rate for patients with LUSC is merely about 18% 3 . Platinum-based systemic chemotherapy is still the standard treatment for LUSC patients, but it often leads to clinical treatment failure due to the development of secondary chemoresistance 4 .…”

Section: Introductionmentioning

confidence: 99%

DLX6-AS1 activated by H3K4me1 enhanced secondary cisplatin resistance of lung squamous cell carcinoma through modulating miR-181a-5p/miR-382-5p/CELF1 axis

Zhao

Wang

Zhu

et al. 2021

Sci Rep

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Cisplatin (CDDP) based chemotherapy is widely used as the first-line strategy in treating non-small cell lung cancer (NSCLC), especially lung squamous cell carcinoma (LUSC). However, secondary cisplatin resistance majorly undermines the cisplatin efficacy leading to a worse prognosis. In this respect, we have identified the role of the DLX6-AS1/miR-181a-5p/miR-382-5p/CELF1 axis in regulating cisplatin resistance of LUSC. qRT-PCR and Western blot analysis were applied to detect gene expression. Transwell assay was used to evaluate the migration and invasion ability of LUSC cells. CCK-8 assay was used to investigate the IC50 of LUSC cells. Flow cytometry was used to test cell apoptosis rate. RNA pull-down and Dual luciferase reporter gene assay were performed to evaluate the crosstalk. DLX6-AS1 was aberrantly high expressed in LUSC tissues and cell lines, and negatively correlated with miR-181a-5p and miR-382-5p expression. DLX6-AS1 expression was enhanced by H3K4me1 in cisplatin resistant LUSC cells. Besides, DLX6-AS1 knockdown led to impaired IC50 of cisplatin resistant LUSC cells. Furthermore, DLX6-AS1 interacted with miR-181a-5p and miR-382-5p to regulate CELF1 expression and thereby mediated the cisplatin sensitivity of cisplatin resistant LUSC cells. DLX6-AS1 induced by H3K4me1 played an important role in promoting secondary cisplatin resistance of LUSC through regulating the miR-181a-5p/miR-382-5p/CELF1 axis. Therefore, targeting DLX6-AS1 might be a novel way of reversing secondary cisplatin resistance in LUSC.

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Section: Introductionmentioning

confidence: 99%

“…Methylation of gene promoter regions is often linked to transcriptional silencing, while methylation of gene bodies has the opposite effect. Epigenetic dysregulation has been linked to the early stages of oncogenic transformation in a variety of solid tumors, and it can be used as a biomarker for early detection, systemic sampling, and prognosis in a variety of human cancers (13). Indeed, Haijing Liu et al (14) reported the potential link between EGFR alterations at the multi-omics levels and clinical prognosis by pan-cancer analysis, but the relationship between DNA methylation of EGFR in LUAD and immune infiltration has not been reported.…”

Section: Introductionmentioning

confidence: 99%

EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma

Qin

Yuan

et al. 2021

Front. Oncol.

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BackgroundThe epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD.MethodsTo assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP).ResultsWe found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247.ConclusionOur data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.

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Investigation on the potential of circulating tumor DNA methylation patterns as prognostic biomarkers for lung squamous cell carcinoma

Cited by 9 publications

References 45 publications

Development and validation of a tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients

Development and validation of a tissue-based DNA methylation risk-score model to predict the prognosis of surgically resected pancreatic cancer patients

DLX6-AS1 activated by H3K4me1 enhanced secondary cisplatin resistance of lung squamous cell carcinoma through modulating miR-181a-5p/miR-382-5p/CELF1 axis

EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma

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