DNMT3a expression pattern and its prognostic value in lung adenocarcinoma

Husni, Ryan Edbert; Shiba-Ishii, Aya; Iiyama, Shinji; Shiozawa, Toshihiro; Kim, Yunjung; Nakagawa, Takumi; Sato, Taiki; Kano, Junko; Minami, Yuko; Noguchi, Masayuki

doi:10.1016/j.lungcan.2016.04.018

Cited by 34 publications

(23 citation statements)

References 33 publications

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“…In the same manner, our results exhibited that high expression of DNMT3A negatively correlated with DFS which was in accordance with the previous study that exhibited the higher expression of DNMT3A in glioblastoma significantly decreases survival (Cheray et al, ). In contrast to our results, low expression of DNMT3A was correlated with poor prognosis in lung adenocarcinoma patients (Husni et al, ). Our data revealed that there was an inverse association between DNMT3B expression and survival that was in line with other studies, showing DNMT3B overexpression correlated with poor prognosis in diffuse large B‐cell lymphoma patients (Amara et al, ) and primary acute myeloid leukemia (Niederwieser et al, ).…”

Section: Discussioncontrasting

confidence: 99%

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Jahangiri

Mosaffa

Razavi

et al. 2018

Journal Cellular Physiology

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Tamoxifen is a standard anti-hormone treatment in estrogen receptor positive breast carcinoma patients. Unfortunately, about 50% of patients relapse during treatment. Promoter hypermethylation contributes to the epigenetic modulation of tamoxifen resistance-related genes. To evaluate the contribution of DNMTs expression and their promoter methylation as diagnostic biomarkers in development of breast malignancy and tamoxifen resistance, the present study was designed and 107 breast tumors and normal breast tissues were recruited. Methylation-specific high-resolution melt curve analysis and quantitative RT-PCR were performed to evaluate DNMTs promoter methylation and mRNA expression, respectively. Our results indicated that DNMT3A and DNMT3B promoters were demethylated in breast tumors as compared to control tissues. The mRNA expression levels of all three DNMTs were significantly increased in tumor specimens in comparison to control tissues (p < 0.05). Among tumor tissues, DNMT3A promoter methylation was significantly higher in tamoxifen sensitive patients (p = 0.001). Overexpression of DNMT3A (p = 0.037) and DNMT3B (p < 0.001) mRNA were observed in tamoxifen resistance group. Multivariate logistic regression analysis indicated that low methylation status of DNMT3A and overexpression of DNMT3B could be as independent predictors of disease recurrence. Multivariate Cox regression analysis, revealed that high methylation status of DNMT3A could be an independent and favorable predictor for disease free survival (p = 0.002) and overall survival (p = 0.026); high expression of DNMT1 (p = 0.03) remained significant and unfavorable predictive factor for overall survival. In conclusion, our data for the first time indicated that low methylation status of DNMT3A promoter and overexpression of DNMT3B could contribute to disease recurrence in tamoxifen-treated breast cancer patients.

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Section: Discussioncontrasting

confidence: 99%

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Jahangiri

Mosaffa

Razavi

et al. 2018

Journal Cellular Physiology

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“…The Notch signaling pathway has an important regulatory role in a variety of tumor stem cells. Mutations in DNMT3a and NOTCH4 have been reported to be associated with better prognosis in patients with LUAD and NSCLC, respectively 73 , 74 . Similarly, the EGFR-TKI sensitivity of patients with these indicates a good prognosis.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib

Shang

Liu

et al. 2020

Sci Rep

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Lung cancer is the leading causes of cancer-related death worldwide. Precise treatment based on next-generation sequencing technology has shown advantages in the diagnosis and treatment of lung cancer. This cohort study included 371 lung cancer patients. The lung cancer subtype was related to the smoking status and sex of the patients. The most common mutated genes were TP53 (62%), EGFR (55%), and KRAS (11%). The mutation frequencies of EGFR, TP53, PIK3CA, NFE2L2, KMT2D, FGFR1, CCND1, and CDKN2A were significantly different between lung adenocarcinoma and lung squamous cell carcinoma. We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR. Tumor mutational burden (TMB) is associated with tumor subtype, age, sex, and smoking status. TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR. EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance. DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.

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“…DNA (Cytosine-5-)-Methyltransferase 3 Alpha (Dnmt3a), an enzyme that catalyzes the transfer of methyl groups to specific CpG structures in DNA, is responsible for de novo DNA methylation, and thus that plays a central role in this mechanism [74]. The methylation status of DNA can either be hyper- or hypomethylated, although global DNA hypomethylation and specific locus hypermethylation frequently co-occur in human cancers [40, 42]. Numerous studies [80–83] showed that DNA methylation has roles in both early and late stages of tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

et al. 2017

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BackgroundAn increasing number of epidemiological and experimental studies have associated exposure to second-hand smoke (SHS) during pregnancy with adverse outcomes in newborns. As we have previously shown in mice, in utero exposure to SHS at critical stages of fetal development, results in altered lung responses and increased disease susceptibility upon re-exposure to irritants (SHS or ovalbumin) in adulthood. In this study, we asked whether the in utero SHS exposure alone is sufficient to alter lung structure and function in adult mice.MethodsPregnant BALB/c mice were exposed from days 6 to 19 of pregnancy to 10 mg/m3 of SHS or HEPA-filtered air. Male and female offspring (n = 13–15/group) were sacrificed at 15 weeks of age. We measured lung function with non-invasive and invasive methods, performed lung morphometric analysis on trichrome-stained lung tissue samples, and assessed lung gene expression via RNA sequencing and protein assays.Results In utero SHS exposure significantly increased mean linear intercept and decreased the surface area per unit volume of the lungs in both males and females, indicating perturbation in alveolar developmental processes. Tidal volume, minute volume and inspiratory capacity were significantly decreased compared with the controls only in male mice exposed in utero to SHS, suggesting that males are more sensitive than females to an SHS insult during lung development. This also suggests that in our model, lung structure changes may be necessary but are not sufficient to impair lung function. SERPINA1A, the mouse ortholog of human α1-antitrypsin, deficiency of which is a known genetic risk factor for emphysema, was down-regulated at the protein level in the in utero SHS-exposed mice. Additionally, DNMT3A protein expression was dysregulated, indicating that DNA methylation occurred in the lungs.ConclusionsOur results indicate that in utero SHS exposure alone alters both lung function and structure well into adulthood (15 weeks) in male mice. Furthermore, lung function alterations in this model are sex-specific, with males being more susceptible to in utero SHS effects. Overall, our data suggest that in utero SHS exposure alone can predispose to adult lung diseases.

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DNMT3a expression pattern and its prognostic value in lung adenocarcinoma

Cited by 34 publications

References 33 publications

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Altered DNA methyltransferases promoter methylation and mRNA expression are associated with tamoxifen response in breast tumors

Comprehensive genomic profile of Chinese lung cancer patients and mutation characteristics of individuals resistant to icotinib/gefitinib

Sex-specific lung functional changes in adult mice exposed only to second-hand smoke in utero

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