Genetic variants in histone modification regions are associated with the prognosis of lung adenocarcinoma
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ABSTRACT:
SUBMITTER: Kang H
PROVIDER: S-EPMC8563968 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveThis study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma.MethodsPotentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy.ResultsAmong the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36-0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09-1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients.ConclusionThis study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.
| S-EPMC9932833 | biostudies-literature
Project description:Genetic variants in regulatory regions of some miRNAs might be associated with lung cancer risk and survival. We performed a case-control study including 1341 non-small cell lung cancer (NSCLC) cases and 1982 controls to evaluate the associations of 7 potentially functional polymorphisms in several differently expressed miRNAs with NSCLC risk. Each SNP was also tested for the association with overall survival of 1001 NSCLC patients. We identified that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a were significantly associated with NSCLC risk [odds ratio (OR) = 1.17, 95% confidence interval (CI) = 1.06-1.30, P = 0.002; OR = 0.88, 95% CI = 0.80-0.98, P = 0.017; respectively]. However, no significant association between variants and NSCLC death risk was observed in survival analysis. Functional annotation showed that both rs9660710 and rs763354 were located in regulatory elements in lung cancer cells. Compared to normal tissues, miR-200a-3p, miR-200a-5p, miR-200b-3p, miR-200b-5p and miR-429 were significantly increased in The Cancer Genome Atlas (TCGA) Lung Adenocarcinoma (LUAD) tumors, whereas miR-30a-3p and miR-30a-5p were significantly decreased in tumors (all P < 0.05). Furthermore, we observed that rs9660710 is an expression quantitative trait locus (eQTL) or methylation eQTL for miR-429 expression in TCGA normal tissues. Our results indicated that rs9660710 in miR-200b/200a/429 cluster and rs763354 in miR-30a might modify the susceptibility to NSCLC.
| S-EPMC5216992 | biostudies-literature
Project description:Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD.
| S-EPMC7235245 | biostudies-literature
Project description:ObjectivesWe postulated that ventilation-perfusion (V/Q) relationships within the lung might influence where lung cancer occurs. To address this hypothesis we evaluated the location of lung adenocarcinoma, by both tumor lobe and superior-inferior regional distribution, and associated variables such as emphysema.Materials and methodsOne hundred fifty-nine cases of invasive adenocarcinoma and adenocarcinoma with lepidic features were visually evaluated to identify lobar or regional tumor location. Regions were determined by automated division of the lungs into three equal volumes: (upper region, middle region, or lower region). Automated densitometry was used to measure radiographic emphysema.ResultsThe majority of invasive adenocarcinomas occurred in the upper lobes (69%), with 94% of upper lobe adenocarcinomas occurring in the upper region of the lung. The distribution of adenocarcinoma, when classified as upper or lower lobe, was not different between invasive adenocarcinoma and adenocarcinoma with lepidic features (formerly bronchioloalveolar cell carcinoma, P = 0.08). Regional distribution of tumor was significantly different between invasive adenocarcinoma and adenocarcinoma with lepidic features (P = 0.001). Logistic regression analysis with the outcome of invasive adenocarcinoma histology was used to adjust for confounders. Tumor region continued to be a significant predictor (OR 8.5, P = 0.008, compared to lower region), whereas lobar location of tumor was not (P = 0.09). In stratified analysis, smoking was not associated with region of invasive adenocarcinoma occurrence (P = 0.089). There was no difference in total emphysema scores between invasive adenocarcinoma cases occurring in each of the three regions (P = 0.155). There was also no difference in the distribution of region of adenocarcinoma occurrence between quartiles of emphysema (P = 0.217).ConclusionInvasive adenocarcinoma of the lung is highly associated with the upper lung regions. This association is not related to smoking, history of COPD, or total emphysema. The regional distribution of invasive adenocarcinoma may be due to V/Q relationships or other local factors.
| S-EPMC4004700 | biostudies-literature
Project description:PURPOSE Differences in cellular levels of histone modifications have predicted clinical outcome in certain cancers. Here, we studied the prognostic and predictive value of three histone modifications in pancreatic adenocarcinoma. METHODS Tissue microarrays (TMAs) from two pancreatic adenocarcinoma cohorts were examined, including those from a 195-patient cohort from Radiation Therapy Oncology Group trial RTOG 9704, a multicenter, phase III, randomized treatment trial comparing adjuvant gemcitabine with fluorouracil and a 140-patient cohort of patients with stage I or II cancer from University of California, Los Angeles Medical Center. Immunohistochemistry was performed for histone H3 lysine 4 dimethylation (H3K4me2), histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 18 acetylation (H3K18ac). Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were related to clinicopathologic parameters and clinical outcome measures. Results Low cellular levels of H3K4me2, H3K9me2, or H3K18ac were each significant and independent predictors of poor survival in univariate and multivariate models, and combined low levels of H3K4me2 and/or H3K18ac were the most significant predictor of overall survival (hazard ratio, 2.93; 95% CI, 1.78 to 4.82) in the University of California, Los Angeles cohort. In subgroup analyses, histone levels were predictive of survival specifically for those patients with node-negative cancer or for those patients receiving adjuvant fluorouracil, but not gemcitabine, in RTOG 9704. CONCLUSION Cellular levels of histone modifications define previously unrecognized subsets of patients with pancreatic adenocarcinoma with distinct epigenetic phenotypes and clinical outcomes and represent prognostic and predictive biomarkers that could inform clinical decisions, including the use of fluorouracil chemotherapy.
| S-EPMC2834495 | biostudies-literature
Project description:BackgroundThe incidence rate of lung adenocarcinoma (LUAD) is rapidly increasing. Recent studies have reported that histone acetylation modification plays an important role in the occurrence and development of tumors. However, the potential role of modification of histone acetylation modification in the development of tumor immune microenvironment is still unclear.MethodsIn this study, we comprehensively evaluated the acetylation modification patterns of LUAD samples obtained from various different databases based on 36 histone modification regulators, and constructed a prognostic model based on The Cancer Genome Atlas (TCGA) LUAD cohort using the Cox regression method. The close relationship between histone acetylation and tumor immune characteristics was further studied, including immune infiltration, immune escape and immunotherapy. Finally, we combined three cohort (GSE30219, GSE72094 and GSE50081) from Gene Expression Omnibus (GEO) database to verify the above results.ResultsWe analyzed the expression, mutation and interaction of 36 histone acetylation regulated genes. After Univariate Cox regression analysis and least absolute shrinkage and selection operator regression (LASSO), 5 genes (KAT2B, SIRT2, HDAC5, KAT8, HDAC2) were screened to establish the prognosis model and calculate the risk score. Then, patients in the TCGA cohort were divided into high- and low-risk groups based on the risk scores. Further analysis indicated that patients in the high-risk group exhibited significantly reduced overall survival (OS) compared with those in the low-risk group. The high- and low-risk groups exhibited significant differences in terms of tumor immune characteristics, such as immune infiltration, immune escape and immunotherapy. The high-risk group had lower immune score, less immune cell infiltration and higher clinical stage. Moreover, multivariate analysis revealed that this prognostic model might be a powerful prognostic predictor for LUAD. In addition, drugs sensitive for this classification were identified. Finally, the efficacy of the prognostic model was validated by cohort (GSE30219, GSE72094 and GSE50081) from GEO database.ConclusionsOur study provided a robust signature for predicting changing prognosis of patients with LUAD. Thus, it appears to be a potentially useful prognostic tool. Moreover, the important relationship between histone acetylation and tumor immune microenvironment was revealed.
| S-EPMC9641363 | biostudies-literature
Project description:Aberrant epidermal growth factor receptor (EGFR) signaling in non-small cell lung cancer (NSCLC) is linked to tumor progression, metastasis and poor survival rates. Here we report the role of Cdc42-interacting protein 4 (CIP4) in the regulation of NSCLC cell invasiveness and tumor metastasis. CIP4 was highly expressed in a panel of NSCLC cell lines and normal lung epithelial cell lines. Stable knockdown (KD) of CIP4 in lung adenocarcinoma H1299 cells, expressing wild-type EGFR, led to increased EGFR levels on the cell surface and defects in sustained activation of Erk kinase in H1299 cells treated with EGF. CIP4 localized to leading edge projections in NSCLC cells, and CIP4 KD cells displayed defects in EGF-induced cell motility and invasion through extracellular matrix. This correlated with reduced expression and activity of matrix metalloproteinase-2 (MMP-2) in CIP4 KD cells compared with control. In xenograft assays, CIP4 silencing had no effect on tumor growth but resulted in significant defects in spontaneous metastases to the lungs from these subcutaneous tumors. This correlated with reduced expression of the Erk target gene Zeb1 and the Zeb1 target gene MMP-2 in CIP4 KD tumors compared with control. CIP4 also enhanced rates of metastasis to the liver and lungs in an intrasplenic experimental metastasis model. In human NSCLC tumor sections, CIP4 expression was elevated greater than or equal to twofold in 43% of adenocarcinomas and 32% of squamous carcinomas compared with adjacent normal lung tissues. Analysis of microarray data for NSCLC patients also revealed that high CIP4 transcript levels correlated with reduced overall survival. Together, these results identify CIP4 as a positive regulator of NSCLC metastasis and a potential poor prognostic biomarker in lung adenocarcinoma.
| S-EPMC4978543 | biostudies-literature
Project description:While much attention has been focused on chromatin at promoters and exons, human genes are mostly composed of intronic sequences. Analyzing published surveys of nucleosomes and 41 chromatin marks in humans, we identified histone modifications specifically associated with 5' intronic sequences, distinguishable from promoter marks and bulk nucleosomes. These intronic marks were spatially reciprocal to trimethylated histone H3 Lys36 (H3K36me3), typically transitioning near internal exons. Several marks transitioned near bona fide exons, but not near nucleosomes at exon-like sequences. Therefore, we examined whether splicing affects histone marking. Even with considerable changes in regulated alternative splicing, histone marks were stable. Notably, these findings are consistent with exon definition influencing histone marks. In summary, we show that the location of many intragenic marks in humans can be distilled into a simple organizing principle: association with 5' intronic or 3' exonic regions.
| S-EPMC3057557 | biostudies-literature
Project description:Background:Lung adenocarcinoma (LUAD), as the main subtype of lung cancer, is one of the common causes of cancer-related deaths worldwide. The AHNAK family is correlated with cell structure and migration, cardiac calcium channel signaling, and tumor metastasis. Previous studies showed AHNAK2 could promote tumor progression and cell migration in melanoma and renal clear cell carcinoma. However, the role of AHNAK2 in LUAD remains unknown. Methods:We examined the levels of AHNAK2 in pathological specimens and the database of Clinical Proteomic Tumor Analysis Consortium-Lung adenocarcinoma (CPTAC-LUAD), The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA-LUAD), Gene Expression Omnibus dataset (GSE72094, GSE26939), and The Genotype-Tissue Expression (GTEx) of lung tissue samples. Univariate Cox regression, multivariate Cox regression, and Kaplan-Meier survival analysis were performed to reveal the relationship between AHNAK2 and prognosis. A nomogram was constructed to predict 2- or 3-year overall survival and validated via calibration curves, receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA). Furthermore, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to explore the functional role of AHNAK2 in lung adenocarcinoma. Finally, by transfecting siRNA, we examined the regulatory effect of AHNAK2 on cell migration. Results:The expression of AHNAK2 was upregulated in tumor samples and correlated with poor prognosis in LUAD patients. Nomogram with AHNAK2 and clinical parameters showed a good prediction in overall survival (OS), especially the 2-year OS. In addition, functional analyses and wound healing assay suggested that AHNAK2 might be involved in the regulation of migration in LUAD. Conclusion:In summary, our study showed that AHNAK2 might be a novel biomarker in LUAD and revealed the potential mechanism of AHNAK2 in LUAD progression which could provide new insights for target therapy.
| S-EPMC7456490 | biostudies-literature
Project description:In the study, we obtained 36 pairs of lung adenocarcinoma (LUAD) tissues and adjacent non-tumorous tissues. Then, we chose a specific hub-target gene of miRNA and used qRT-PCR to evaluate the expression of PECAM1. We found that the expression level of PECAM1 mRNA in LUAD was significantly lower than that in adjacent nontumor tissues (P<0.0001). Univariate and multivariate analyses were conducted on 481 LUAD patients from The Cancer Genome Atlas (TCGA) according to the Cox proportional hazard regression model to evaluate the impact of PECAM1 expression and other clinicopathological factors on survival. The results showed that the low expression of PECAM1 was an important independent predictor of poor overall survival (HR, 0.704; 95% CI, 0.518-0.957; P = 0.025). Based on the Tumor Immune Estimation Resource (TIMER) database, the relationship between PECAM1 expression and B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration was weak in LUAD (P<0.01). In particular, a more significant positive correlation between PECAM1 expression and HLA-complex members, CD1C, NRP1, and ITGAX expression in dendritic cell was detected in LUAD. The mechanism which PECAM1 involved in the development of LUAD may be closely related to changes in the immune microenvironment.
| S-EPMC7906143 | biostudies-literature