AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality

Grieshober, Laurie; Graw, Stefan; Barnett, Matt J.; Thornquist, Mark; Goodman, Gary E.; Chen, Chu; Koestler, Devin C.; Marsit, Carmen J.; Doherty, Jennifer A.

doi:10.1186/s12885-020-07407-x

Cited by 25 publications

(24 citation statements)

References 40 publications

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“…Lung cancer often originates from bronchial mucosa or gland, and is a malignant tumor with relative high mortality [ 1 , 2 ]. In 2018, the mortality of male lung cancer ranked the highest in the world, while lung cancer incidence rate was the highest among women, and the mortality rate was only second [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

Luo

Zhuo

et al. 2021

BMC Pulm Med

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Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.

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Section: Introductionmentioning

confidence: 99%

POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

Luo

Zhuo

et al. 2021

BMC Pulm Med

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“…We estimated methylation-based blood cell type proportions from archival samples based on CpGs that were recently identi ed using deconvolution algorithms applied to EPIC 850K CpG array data (i.e. EPIC-optimized) by Salas et al [40], in contrast to our prior work in which we used CpGs that were identi ed using the 450K CpG array data [46,47]. Cell type estimates, and therefore mdNLR, obtained from the two arrays are highly correlated in our study (mdNLR Spearman r = 0.99, P = 7.0E-301) and in the literature [40].…”

Section: Discussionmentioning

confidence: 99%

“…Our study included 372 individuals diagnosed with lung cancer between 1994 and 2013 from the multicenter β-Carotene and Retinol E cacy Trial (CARET) of heavy smokers at high risk for lung cancer [45], which we have described previously [46].…”

Section: Methodsmentioning

confidence: 99%

“…We assayed DNA methylation in the archival whole blood samples using the Illumina HumanMethylationEPIC BeadArray, followed by standard normalization and preprocessing procedures [46,47]. We estimated proportions of six blood cell types (B cell, CD4T, CD8T, natural killer (NK), neutrophil, monocyte) for each case in our normalized methylation dataset using constrained projection of the EPIC IDOL-optimized cell mixture deconvolution matrix with the "projectCellType_CP" function from the FlowSorted.Blood.EPIC package in R [40].…”

Section: Methodsmentioning

confidence: 99%

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Pre-diagnosis neutrophil-to-lymphocyte ratio and mortality in individuals who develop lung cancer

Grieshober

Graw

Barnett

et al. 2021

Preprint

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Purpose The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that has been reported to be associated with survival after chronic disease diagnoses, including lung cancer. We hypothesized that the inflammatory profile reflected by pre-diagnosis NLR, rather than the well-studied pre-treatment NLR at diagnosis, may be associated with increased mortality after lung cancer is diagnosed in high risk heavy smokers.Methods We examined associations between pre-diagnosis methylation derived-NLR (mdNLR) and lung cancer-specific and all-cause mortality in 372 lung cancer cases from the β-Carotene and Retinol Efficacy Trial (CARET). Cox proportional hazards models were adjusted for age, sex, smoking status, pack years, and time between blood draw and diagnosis, and stratified by stage of disease. Models were run separately by histotype.Results Among those who developed small cell lung cancer (SCLC, N = 81), individuals with pre-diagnosis mdNLR in the highest quartile had 2.5-fold increased mortality compared to those in the lowest quartile. For each unit increase in pre-diagnosis mdNLR, we observed 22–23% increased mortality in SCLC (SCLC-specific hazard ratio [HR] = 1.23, 95% confidence interval [CI]: 1.02, 1.48; all-cause HR = 1.22, 95% CI: 1.01, 1.46). SCLC associations were strongest for current smokers at blood draw (Interaction Ps = 0.03). mdNLR was not associated with mortality for individuals diagnosed with adenocarcinoma (N = 148) or squamous cell carcinoma (N = 115).Conclusion Our findings suggest that increased mdNLR, representing a systemic inflammatory profile on average 4.5 years before a SCLC diagnosis, may be associated with mortality in heavy smokers who go on to develop SCLC but not other lung cancer histotypes.

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“…Multiple studies (Grieshober et al 2020; Philibert et al 2020) have found that hypomethylation of AHRR , which encodes the Aryl-Hydrocarbon Receptor Repressor, is strongly associated with smoking in several tissues. AHRR modulates responses to dioxin toxicity and is involved in regulation of cell growth.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data

Flynn

Chang

Nugent

et al. 2021

Preprint

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Smoking greatly reduces life expectancy in both men and women, but with different patterns of morbidity. After adjusting for smoking history, women have higher risk of respiratory effects and diabetes from smoking, while men show greater mortality from smoking-related cancers. While many smoking-related sex differences have been documented, the underlying molecular mechanisms are not well understood. To date, identification of sex differences in response to smoking has been limited to a small number of studies and the resulting smoking-related effects require further validation. Publicly available gene expression data present a unique opportunity to examine molecular-level sex and smoking effects across many tissues and studies. We performed a systematic search to identify smoking-related studies from healthy tissue samples and found 31 separate studies as well as an additional group of overlapping studies that in total span 2,177 samples and 12 tissues. These samples and studies were overall male-biased. In smoking, while effects appeared to be somewhat tissue-specific and largely autosomal, we identified a small number of genes that were consistently differentially expressed across tissues, including AHRR and GZMH. We also identified one gene, AKR1C3, encoding an aldo-keto reductase, which showed strong opposite direction, smoking-related effects in blood and airway epithelium, with higher expression in airway epithelium and lower expression in blood of smokers versus non-smokers. By contrast, at similar significance thresholds, sex-related effects were entirely sex chromosomal and consistent across tissues, providing evidence of stronger effects of smoking than sex on autosomal expression. Due to sample size limitations, we only examined interaction effects in the largest study, where we identified 30 genes with sex differential effects in response to smoking, only one of which, CAPN9, replicated in a held-out analysis. Overall these results present a comprehensive analysis of smoking-related effects across tissues and an initial examination of sex differential smoking effects in public gene expression data.

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AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality

Cited by 25 publications

References 40 publications

POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

Pre-diagnosis neutrophil-to-lymphocyte ratio and mortality in individuals who develop lung cancer

Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data

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