Fine mapping in <i>TERT‐CLPTM1L</i> region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Li, Zhihua; Pu, Zhening; Fan, Jingyi; Li, Ni; Zhu, Meng; Zhang, Jiahui; Wang, Yuzhuo; Geng, Liguo; Yang, Cheng; Ma, Hongxia; Jin, Guangfu; Dai, Juncheng; Hu, Zhibin; Shen, Hongbing

doi:10.1002/mc.22843

Cited by 5 publications

(7 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although ERβ plays an important role in CLPTM1L-mediated radioresistance, knockdown of ERβ is not a feasible radiosensitizing method at the moment, because multiple functions of ERβ were still elusive in lung cancer. The present results and those of previous studies suggest that CLPTM1L expression is higher in radioresistant NSCLC cells than in radiosensitive cells, and it is considerably higher than that in normal cells [ 30 , 98 ]. IR upregulated CLPTM1L only in radioresistant cells, whereas it had no effect in most radiosensitive cells.…”

Section: Discussionsupporting

confidence: 78%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

View full text Add to dashboard Cite

Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

show abstract

Section: Discussionsupporting

confidence: 78%

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Chen

Jiang

et al. 2020

Cell Commun Signal

View full text Add to dashboard Cite

show abstract

“…Previous studies also reported that the impact of TERT variation in Asians was stronger than that in Caucasians 45 , 55 . Another study showed that rs2735947 was the most significant SNP in the Caucasians rather than rs2736100 49 . Our findings also confirmed that the C allele and "C" genotype frequencies were indeed higher in Asians than in Caucasians, suggesting that Asians may have longer telomeres that leads to an increased risk of LC.…”

Section: Discussionmentioning

confidence: 99%

“…These evidences imply that the C allele upregulates TERT expression, maintains and prolongs telomere length, and thus increases the risk of LC. In addition, some studies have conducted racial stratification analysis for different types of LC and proved that the influence of TERT variants in Asians is stronger than that in Caucasians 45 , 49 . These results in turn imply that the frequency of TERT rs2736100 variants varies across ethnic populations.…”

Section: Introductionmentioning

confidence: 99%

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

Huang

et al. 2023

Sci Rep

View full text Add to dashboard Cite

The rs2736100 (A > C) polymorphism of the second intron of Telomerase reverse transcriptase (TERT) has been confirmed to be closely associated with the risk of Lung cancer (LC), but there is still no unified conclusion on the results of its association with LC. This study included Genome-wide association studies (GWAS) and case–control studies reported so far on this association between TERT rs2736100 polymorphism and LC to clarify such a correlation with LC and the differences in it between different ethnicities and different types of LC. Relevant literatures published before May 7, 2022 on ‘TERT rs2736100 polymorphism and LC susceptibility’ in PubMed, EMbase, CENTRAL, MEDLINE databases were searched through the Internet, and data were extracted. Statistical analysis of data was performed in Revman5.3 software, including drawing forest diagrams, drawing funnel diagrams and so on. Sensitivity and publication bias analysis were performed in Stata 12.0 software. The C allele of TERT rs2736100 was associated with the risk of LC (Overall population: [OR] = 1.21, 95%CI [1.17, 1.25]; Caucasians: [OR] = 1.11, 95%CI [1.06, 1.17]; Asians: [OR] = 1.26, 95%CI [1.21, 1.30]), and Asians had a higher risk of LC than Caucasians (C vs. A: Caucasians: [OR] = 1.11 /Asians: [OR]) = 1.26). The other gene models also showed similar results. The results of stratified analysis of LC patients showed that the C allele was associated with the risk of Non-small-cell lung carcinoma (NSCLC) and Lung adenocarcinoma (LUAD), and the risk of NSCLC and LUAD in Asians was higher than that in Caucasians. The C allele was associated with the risk of Lung squamous cell carcinoma (LUSC) and Small cell lung carcinoma(SCLC) in Asians but not in Caucasians. NSCLC patients ([OR] = 1.27) had a stronger correlation than SCLC patients ([OR] = 1.03), and LUAD patients ([OR] = 1.32) had a stronger correlation than LUSC patients ([OR] = 1.09).In addition, the C allele of TERT rs2736100 was associated with the risk of LC, NSCLC and LUAD in both smoking groups and non-smoking groups, and the risk of LC in non-smokers of different ethnic groups was higher than that in smokers. In the Asians, non-smoking women were more at risk of developing LUAD. The C allele of TERT rs2736100 is a risk factor for LC, NSCLC, and LUAD in different ethnic groups, and the Asian population is at a more common risk. The C allele is a risk factor for LUSC and SCLC in Asians but not in Caucasians. And smoking is not the most critical factor that causes variation in TERT rs2736100 to increase the risk of most LC (NSCLC, LUAD). Therefore, LC is a multi-etiological disease caused by a combination of genetic, environmental and lifestyle factors.

show abstract

“…The detailed information about the study subjects in NJMU GWAS was described previously [9]. Genotype imputation for NJMU GWAS was performed using IMPUTE2 and Shapeit v2 with the 1000 Genomes Project (the Phase III integrated variant set release, across 2504 samples) as the reference [14].…”

Section: Study Subjectsmentioning

confidence: 99%

Systematic analysis of genetic variants in cancer-testis genes identified two novel lung cancer susceptibility loci in Chinese population

Tang

Wen

et al. 2020

J. Cancer

Self Cite

View full text Add to dashboard Cite

Cancer-testis (CT) genes played important roles in the progression of malignant tumors and were recognized as promising therapeutic targets. However, the roles of genetic variants in CT genes in lung cancer susceptibility have not been well depicted. This study aimed to evaluate the associations between genetic variants in CT genes and lung cancer risk in Chinese population. A total of 22,556 qualified SNPs from 268 lung cancer associated CT genes were initially evaluated based on our previous lung cancer GWAS (Genome-wide association studies) with 2,331 cases and 3,077 controls. As a result, 17 candidate SNPs were further genotyped in 1,056 cases and 1,053 controls using Sequenom platform. Two variants (rs6941653, OPRM1,

show abstract

Fine mapping in TERT‐CLPTM1L region identified three independent lung cancer susceptibility signals: A large‐scale multi‐ethnic population study

Cited by 5 publications

References 52 publications

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

Ethnicity-specific association between TERT rs2736100 (A > C) polymorphism and lung cancer risk: a comprehensive meta-analysis

Systematic analysis of genetic variants in cancer-testis genes identified two novel lung cancer susceptibility loci in Chinese population

Contact Info

Product

Resources

About