Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and <i>TP53</i> mutations

Tekpli, Xavier; Landvik, Nina E.; Skaug, Vidar; Gulsvik, Amund; Haugen, Aage; Zienolddiny, Shanbeh

doi:10.1002/ijc.27870

Cited by 14 publications

(12 citation statements)

References 37 publications

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“…The GWAS SNPs at 15q25.1 were reported to be associated with total expression levels and multiple isoforms of CHRNA5 in normal lung tissue samples 37,38 . The GWAS SNPs at the other four loci have not been reported to be associated with the total expression of nearby genes.…”

Section: Resultsmentioning

confidence: 99%

Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

et al. 2014

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The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters, and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, 4 of the 5 established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.

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Section: Resultsmentioning

confidence: 99%

Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

et al. 2014

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“…Importantly, cigarette smoking, which is one of the main causes of NSCLC and has also been related to prognosis in NSCLC patients treated with cisplatin and gemcitabine or cisplatin and pemetrexed [26], leads to more copy number alterations, which may be mediated by the genome instability [27]. A recent study showed that nicotinic acetylcholine receptor alpha3, alpha5, and beta4 genes (CHRNA3, CHRNA5, and CHRNB4) cluster at the 15q25.1 lung cancer susceptibility locus, and four variants (rs3829787, rs3841324, rs588765, and rs3743073) were associated with differential levels of genetic aberrations, while three haplotypes were associated with CHRNA5 mRNA levels, susceptibility to NSCLC, smoking-related DNA alterations, and TP53 mutations [28]. Genetic differences resulting in interindividual variation in DNA repair capacity may indeed account for susceptibility of the lung cells to the genotoxic agents leading to somatic mutations, and individuals who smoke and have polymorphisms that may result in deficient DNA repair are at a greater risk of TP53 mutations.…”

Section: Pharmacogenetics Of Nsclc: Which Genes Copy Number Variatiomentioning

confidence: 99%

On the pharmacogenetics of non-small cell lung cancer treatment

Santarpía

Rolfo

Peters

et al. 2016

Expert Opinion on Drug Metabolism & Toxicology

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Introduction. Despite many clinical efforts, non-small-cell lung cancer (NSCLC) has a dismal 5-year survival rate of 16%, and high incidence of recurrence. The success of biologically targeted agents, as well as the activity of well-established chemotherapeutic regimens, has been limited by inherited/ acquired resistance, and biomarkers to adapt the prescription of anticancer drugs to patients' features are urgently warranted. Areas covered. In oncology, pharmacogenetics should provide the way to select patients who may benefit from a specific therapy that best match the individual and tumor genetic profile, thus allowing maximum activity and minimal toxicity. The present review summarizes the main findings on NSCLC pharmacogenetics, critically reappraising the most important studies on polymorphisms correlated with outcome of pemetrexed and EGFR-inhibitors, and provides perspective on clinical application of genomic tests for treatment decision-making. Expert Opinion. A major challenge in NSCLC is the identification of subgroups of diseases/patients that will truly benefit from specific treatments. Ideally, convenient and minimally invasive tests to decipher biomarkers of chemosensitivity/resistance and toxicity should be developed alongside novel anticancer treatments. Integration with the latest generation of whole-genome analyses and liquid biopsies as well as prospective validation in large cohorts of patients will overcome the limitations of the traditional pharmacogenetic approaches. ARTICLE HISTORY

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“…Recently, the locus containing two genes encoding nicotine acetylcholine receptor (nAChR) subunits, CHRNA3 and CHRNA5, was shown to be associated with lung cancer risk in Caucasians by three genome-wide association studies [17,19,20]. A decreased survival correlation with lung cancer has been shown because the reduced treatment e cacy and worse survival may be well explained by the nAChRs pathway through CHRNA proteins on tumor cell proliferation, apoptosis, epithelial-mesenchymal transition, and proinvasive and angiogenic effects [21,22]. Our results showed that CHRNA5 was higher expressed in lung adenocarcinoma tissues, and that there is a signi cant association between the expression and clinical characteristics and patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

Expression and Prognostic Significance of the Nicotinic Receptor Cluster on 15q25 about CHRNA5 and PSMA4 mRNA in Lung Adenocarcinoma Utilizing TCGA Datasets

Wang

et al. 2020

Preprint

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Background: Genome-wide association studies of lung cancer have shown a common variation at 15q24-25.1 as a determinant of risk, but the role of specific genes has not been proven. This study aims to explore the expression of mutations and the prognostic significance of 15q25 (CHRNA5 and PSMA4) mRNA in lung adenocarcinoma (LAC) based on immunohistochemistry, TCGA and bioinformatics. Methods: The expression of mutations on chromosome 15q25 of 576 primary LAC patients was selected and survival and gene expression data were extracted from TCGA. The relationship between expression of genes on 15q25 and clinical and prognostic Significance of LAC. An experiment with Beas-2b, A549 and H1299 cell lines was performed to further prove the difference in CHRNA5 and PSMA4 expression between lung cancer and normal cells. Immunohistochemistry data of CHRNA5 and PSMA4 were detected in LAC and normal tissues from 122 patients. Finally, Gene enrichment analysis (GSEA) was conducted to predict the regulatory genes of CHRNA5 and PSMA4. Results: CHRNA5 and PSMA4 are frequently mutated in TCGA (CHRNA5, 1.7%; PSMA4, 1.3%). Besides, the expression of CHRNA5 and PSMA4 was obviously higher in A549 and H1299 cells. And the immunohistochemical staining revealed that the levels of CHRNA5 and PSMA4 were considerably higher in the LAC group than in the normal group. Meanwhile, there was a significant association between high CHRNA5 expression and smoking history (P=0.011), smoking history pack year value (P=0.010). Furthermore, there was a significant correlation between CHRNA5 and PSMA4 expression levels and prognosis (P=0.003; P=0.008), and between higher expression and worse prognosis. GSEA results suggested that between samples with high CHRNA5 and PSMA4 expression were respectively enriched to cell cycle, base excision repair, oxidative phosphorylation, protein export, and aminoacyl tRNA biosynthesis, among others. Conclusions: CHRNA5 and PSMA4 mRNA expression has a significant impact on the clinical and survival of LAC, and they may be a potential target for treating patients with lung adenocarcinoma.

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Functional effect of polymorphisms in 15q25 locus on CHRNA5 mRNA, bulky DNA adducts and TP53 mutations

Cited by 14 publications

References 37 publications

Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

Characterizing the genetic basis of methylome diversity in histologically normal human lung tissue

On the pharmacogenetics of non-small cell lung cancer treatment

Expression and Prognostic Significance of the Nicotinic Receptor Cluster on 15q25 about CHRNA5 and PSMA4 mRNA in Lung Adenocarcinoma Utilizing TCGA Datasets

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