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Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

ABSTRACT: Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407_TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 × 10^-5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493). As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407_TRIM27 methylation in NSCLC. LUSC patients had a higher average pack-year of smoking (37.49_LUAD vs 54.79_LUSC, P = 1.03 × 10^-19) and included a higher proportion of current smokers than LUAD patients (28.24%_LUAD vs 34.09%_LUSC, P = 0.037). cg05293407_TRIM27 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 × 10^-5). We conclude that cg05293407_TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.

SUBMITTER: Ji X

PROVIDER: S-EPMC7607178 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Ji Xinyu X Lin Lijuan L Shen Sipeng S Dong Xuesi X Chen Chao C Li Yi Y Zhu Ying Y Huang Hui H Chen Jiajin J Chen Xin X Wei Liangmin L He Jieyu J Duan Weiwei W Su Li L Jiang Yue Y Fan Juanjuan J Guan Jinxing J You Dongfang D Shafer Andrea A Bjaanaes Maria Moksnes MM Karlsson Anna A Planck Maria M Staaf Johan J Helland Åslaug Å Esteller Manel M Wei Yongyue Y Zhang Ruyang R Chen Feng F Christiani David C DC

Molecular oncology 20200903 11

Tripartite motif containing 27 (TRIM27) is highly expressed in lung cancer, including non-small-cell lung cancer (NSCLC). Here, we profiled DNA methylation of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) tumours from 613 early-stage NSCLC patients and evaluated associations between CpG methylation of TRIM27 and overall survival. Significant CpG probes were confirmed in 617 samples from The Cancer Genome Atlas. The methylation of the CpG probe cg05293407<sub>TRIM27</sub> was ...[more]

PMID: 33448640

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Project description:Epigenome-wide gene-gene (G × G) interactions associated with non-small-cell lung cancer (NSCLC) survival may provide insights into molecular mechanisms and therapeutic targets. Hence, we proposed a three-step analytic strategy to identify significant and robust G × G interactions that are relevant to NSCLC survival. In the first step, among 49 billion pairs of DNA methylation probes, we identified 175 775 G × G interactions with PBonferroni ≤ 0.05 in the discovery phase of epigenomic analysis; among them, 15 534 were confirmed with P ≤ 0.05 in the validation phase. In the second step, we further performed a functional validation for these G × G interactions at the gene expression level by way of a two-phase (discovery and validation) transcriptomic analysis, and confirmed 25 significant G × G interactions enriched in the 6p21.33 and 6p22.1 regions. In the third step, we identified two G × G interactions using the trans-omics analysis, which had significant (P ≤ 0.05) epigenetic cis-regulation of transcription and robust G × G interactions at both the epigenetic and transcriptional levels. These interactions were cg14391855 × cg23937960 (βinteraction = 0.018, P = 1.87 × 10-12 ), which mapped to RELA × HLA-G (βinteraction = 0.218, P = 8.82 × 10-11 ) and cg08872738 × cg27077312 (βinteraction = -0.010, P = 1.16 × 10-11 ), which mapped to TUBA1B × TOMM40 (βinteraction =-0.250, P = 3.83 × 10-10 ). A trans-omics mediation analysis revealed that 20.3% of epigenetic effects on NSCLC survival were significantly (P = 0.034) mediated through transcriptional expression. These statistically significant trans-omics G × G interactions can also discriminate patients with high risk of mortality. In summary, we identified two G × G interactions at both the epigenetic and transcriptional levels, and our findings may provide potential clues for precision treatment of NSCLC.

Project description:BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the established first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, but survival advantages in advanced-stage cases remain modest and show interpatient variability. This study seeks to delineate real-world survival outcomes in stage IV EGFR-mutant NSCLC patients undergoing treatment with EGFR-TKIs and to identify independent prognostic factors impacting overall survival (OS). The findings are expected to be a reference for clinicians in managing advanced lung cancer patients.MethodsClinical characteristics from advanced EGFR-mutant NSCLC patients who received EGFR-TKIs were retrospectively analyzed to investigate the association between clinical factors and overall survival.ResultsThe median OS was 40.60 months (95% confidence interval: 34.72-46.48 months), with expected 1-, 3-, and 5-year OS of 87.2%, 57.8%, and 34.0%, respectively. Patients exhibiting specific characteristics, such as being under 60 years old, having stage IVA disease, adenocarcinoma histology, no liver or brain metastases, negative for neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21 - 1), progastrin-releasing peptide (ProGRP), and those who received chemotherapy and radiotherapy exhibited significantly longer survival times compared to patients with the opposite characteristics (being 60 years or older, having stage IVB or IVC disease, non-adenocarcinoma histology, presence of liver or brain metastases, positive for CEA, NSE, ProGRP, CYFRA 21 - 1, and not receiving chemotherapy or radiotherapy) (P < 0.05). Cox univariate and multivariate analyses identified pathological type, liver metastasis, brain metastasis, NSE, CYFRA 21 - 1, EGFR-TKIs type, radiotherapy, and chemotherapy as independent prognostic factors for patients with stage IV NSCLC treated with EGFR-TKIs.ConclusionsPathological type, liver metastasis, brain metastasis, NSE, and CYFRA 21 - 1 were identified as independent risk factors for stage IV NSCLC patients treated with EGFR-TKIs, while chemotherapy and radiotherapy were determined to be independent protective factors. Taking icotinib or gefitinib, as opposed to osimertinib, was an independent risk factor for advanced NSCLC patients.

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Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

Publications

Epigenetic-smoking interaction reveals histologically heterogeneous effects of TRIM27 DNA methylation on overall survival among early-stage NSCLC patients.

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