Cleft Lip And Palate Transmembrane 1-like Research Articles

Study of genetic variants in chromosome 5p15.33 region in non-smoker lung cancer patients.

Genome-wide association studies have identified that genetic polymorphisms in the telomerase reverse transcrip-tase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes may play important roles in the development of lung cancer in never smokers. This study was aiming to evaluate the associations between the risk of lung cancer in never smokers and single nucleotide polymorphisms in these genes by Real-Time Taqman assay, in forty lung cancer patients and forty apparently healthy age-matched controls selected from the chest department, Kasr Al-Ainy hospital from June 2018 to January 2019. Adenocarcinoma was the most common histopathological subtype of lung cancer in the study patients. Also, the prevalence of females having adenocarcinoma was more common than males. The heterozygous form of the CLPTM1L occurred more frequently in the subjects aged above 46 years (P=0.019). There was a significant association between (rs 2730100) (c. 1574-3777C>A) TERT and CLPTM1L (rs 451360) (c.1532+ 1051C>A) genotypes and the incidence of lung cancer in never smokers, especially adenocarcinoma, a subtype of non-small cell lung carcinoma (NSCLC). Polymorphism in the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1 like (CLPT-M1L) genes may play an important role in the development of NSCLC, especially adenocarcinoma subtype. The two genes are located in the chromosome 5p15.33.

CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells.

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.

CLPTM1L gene rs402710 (C > T) and rs401681 (C > T) polymorphisms associate with decreased cancer risk: a meta-analysis.

Cleft lip and palate transmembrane 1-like (CLPTM1L) gene rs402710 (C > T) and rs401681 (C > T) polymorphisms have been widely studied for their potential relation to cancer risk, but studies have produced conflicting results. To systematically evaluate the association between these two polymorphisms and overall cancer risk, we conducted a comprehensive meta-analysis on all relevant articles found in the PubMed and EMBASE databases published prior to May 1, 2017. There were 26 articles with 28 studies, including 30,770 cases and 34,089 controls, for the rs402710 polymorphism and 38 articles with 48 studies, including 67,849 cases and 328,226 controls, for the rs401681 polymorphism. The pooled results indicated that both rs402710 and rs401681 polymorphisms are significantly associated with decreased overall cancer risk. In our stratification analysis, a significant association of the rs402710 polymorphism with lung and bladder cancers was identified among Asian and Caucasian populations in both hospital-based and population-based studies. The rs401681 polymorphism was significantly associated with a decreased risk of lung cancer, bladder cancer, and basal cell carcinoma in Asians and in hospital-based studies. CLPTM1L gene rs402710 and rs401681 polymorphisms thus have a protective association with various types of cancer, especially lung cancer among Asians.

Abstract B12: CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K

Abstract Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. Tumor cells must endure ER stress caused by microenvironmental, oxidative, energetic, and therapeutic stresses to survive. However, the role of ER stress survival signaling in pancreatic tumorigenesis has not been elucidated. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related target in pancreatic cancer. We recently demonstrated that CRR9/CLPTM1L is overexpressed in 90% of pancreatic ductal adenocarcinomas and associated with poor outcome, while it is not expressed in normal pancreatic ductal epithelium. Furthermore, we have shown that CLPTM1L can confer resistance to chemotherapeutic killing, apoptosis, and anoikis, and is critical for KRas transformation and tumorigenesis. Here, we demonstrate that CLPTM1L interacts with phosphoinositol-3-kinase (PI3K) and the ER stress protein Glucose Related Protein 78 (GRP78) at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt survival signaling. Surface accumulation of both CLPTM1L and GRP78 are induced by ER stress and by chemotherapy in vitro. Subsequent to our recent discovery of the presence of CLPTM1L at the cell surface, we have developed antibody inhibitors of CLPTM1L, which deplete chemotherapy-inducible surface accumulation of CLPTM1L and GRP78, as well as downstream survival signaling through the Akt pathway and Bcl-xL expression. These agents have shown striking anti-tumorigenic efficacy in preclinical models of pancreatic cancer and present a promising therapeutic and chemosensitization approach. Citation Format: Michael James.{Authors}. CLPTM1L and GRP78 interact and promote pancreatic tumor survival under ER-stress and chemoresistance through cell-surface translocation and interaction with PI3K. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B12.

Study of the impact of CLPTM1L on radiosensitivity of lung cancer

Objective To study the correlation of cleft lip and palate transmembrane 1 like (CLPTM1L) expression and radiosensitivity of lung cancer cells. Methods Thiazolyl blue tetrazolium bromide (MTT) and cell colony formation assays were used to determine cell growth and survival. Western Blot assay was employed to measure protein expression. Results The results demonstrated a negative correlation between the CLPTM1L expression level and radiosensitivity of lung cancer cells. A lower radiosensitivity in lung cancer cells containing high level of CLPTM1L expression, and vice versa. Enforced expression of CLPTM1L resulted in a significant reduction of radiosensitivity in lung cancer cells irradiated with γ-rays. On the contrary, a marked elevation of radiosensitivity was observed in lung cancer cells transfected with CLPTM1L siRNA. Conclusions CLPTM1L may be a novel target gene in mediating radiosensitivity of lung cancer cells. Key words: Cleft lip and palate transmembrane 1 like; Radiation tolerance; Lung neoplasms; γ-rays

Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling.

We and others have recently shown cisplatin resistance-related protein 9 (CRR9)/Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L) to affect survival and proliferation in lung and pancreatic tumor cells. Our research has indicated that CLPTM1L affects multiple survival signaling pathways in tumor cells under oncogenic, genotoxic, and microenvironmental stress. We have confirmed the association of CLPTM1L with pancreatic cancer by demonstrating overexpression of CLPTM1L in pancreatic tumors and poor survival in patients with high tumor expression of CLPTM1L. Predicting a transmembrane structure, we determined that CLPTM1L could be targeted at the plasma membrane. Herein, we describe the development of mAbs targeting CLPTM1L. Lead antibodies inhibited surface accumulation of CLPTM1L, Akt phosphorylation, anchorage-independent growth, and chemotherapeutic resistance in lung and pancreatic tumor cells. Gemcitabine promoted a physical interaction between CLPTM1L and p110α in pancreatic tumor cells, which was inhibited by anti-CLPTM1L. In vivo treatment with anti-CLPTM1L robustly inhibited the growth of both lung and pancreatic adenocarcinoma xenografts. The efficacy of anti-CLPTM1L correlated with specific epitopes representing important targets in human cancers, particularly those driven by KRas, for which effective targeted therapies have been elusive. This study is the first to report cell-surface exposure of the tumor survival protein CLPTM1L and inhibition of the function of surface CLPTM1L with novel, systematically developed inhibitory mAbs establishing proof of concept of clinically practical agents inhibiting this compelling new tumor survival target in cancer. Mol Cancer Ther; 15(5); 985-97. ©2016 AACR.

CLPTM1L polymorphism as a protective factor for lung cancer: a case-control study in southern Chinese population.

Variants of the cleft lip and palate trans-membrane 1 like (CLPTM1L) gene, located on chromosome 5p15.33, were previously determined to influence lung cancer susceptibility. Here, we performed a case-control study to examine the potential association of CLPTM1L single nucleotide polymorphisms (SNPs) with lung cancer in a Chinese Han population. We selected four SNPs in the CLPTM1L gene that were previously reported to be associated with lung cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the strength of the relationship between each CLPTM1L SNP and lung cancer risk. Allelic model analysis revealed that the minor alleles of all four SNPs were significantly associated with decreased lung cancer risk. Similar significant results were detected using genetic model analysis. In addition, we observed a protective effect of haplotype "TT" in the CLPTM1L gene. Our results verified that certain CLPTM1L polymorphisms are protective factors against lung cancer in a southern Chinese Han population and may be potential diagnostic and molecular markers for lung cancer patients.

Rs401681 polymorphism in TERT-CLPTM1L was associated with bladder cancer risk: A meta-analysis.

Genome-wide association studies have identified a number of genetic variants of telomerase reverse transcriptase (TERT), cleft lip and palate transmembrane1-like (CLPTM1L) associated with the risk of bladder cancer. Rs401681 polymorphism in TERT-CLPTM1L was of special interest for bladder cancer risk, whereas the results were inconclusive. Publications illustrating the association between rs401681 polymorphism and bladder cancer risk were collected from the Embase, PubMed and Google scholar. Three independent reviewers worked on the data extraction. The meta-analysis was performed by STATA 12.0. The odds ratio (OR) with 95% confidence interval (CI) was calculated for these data. Six case-control studies were retrieved reporting a total of 9196 bladder cancer patients and 42570 controls. The strength of the relevance between rs401681 polymorphism and bladder cancer risk was evaluated by Stata 12.0 software. Rs401681[C] allele was identified marginally associated with increased bladder cancer risk, with per allele OR of 1.132 (95% CI=1.080-1.187, P heterogeneity=0.701); in the stratified analysis by ethnicity, the increased cancer risk was revealed in Asian and Caucasian groups. Moreover, we also revealed that rs401681 polymorphism was associated with an increased risk of bladder cancer in Asian population with three publications under allele model (OR=3.722, 95% CI=1.311-10.568, P=0.014), whereas a decreased risk was identified in homozygote model (OR=0.692, 95 % CI=0.513-0.934, P= 0.016) and recessive model (OR=0.728, 95% CI=0.541-0.980, P=0.036). In summary, our study provided evidence that rs401681 polymorphism is associated with the risk of bladder cancer.

Association of genetic polymorphisms in TERT-CLPTM1L with lung cancer in a Chinese population.

Genome-wide association studies in several ethnic groups have reported that polymorphisms of the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, located on 5p15.33, are associated with susceptibility to lung cancer. However, whether genetic variants of TERT-CLPTM1L are associated with an increased risk of lung cancer in the Chinese Han population is unknown. This study examined associations between five single nucleotide polymorphisms (SNPs) of TERT-CLPTM1L (rs402710, rs401681, rs465498, rs4975616, and rs2736100) and lung cancer in a Chinese Han population in the Hubei Province. The five SNPs were detected using the Sequenom MassArray(®) iPLEX System in 304 lung cancer patients and 319 controls. Of the five SNPs, rs4975616 did not conform to Hardy-Weinberg equilibrium in the controls. Only rs2736100 was significantly (P = 0.034) associated with an increased risk of lung cancer. In the linkage disequilibrium analyses, a block of strong linkage disequilibrium was observed between rs401681 and rs465498 (D' = 0.986; r(2) = 0.546). No linkage disequilibrium between rs2736100 and the other three SNPs was found. In the haplotype analyses, the frequencies of the TTCT haplotype in rs402710, rs401681, rs465498, and rs2736100 differed significantly between case and control subjects (odds ratio = 0.56; 95% confidence interval, 0.36-0.88; P = 0.012). The results of this study suggested that rs2736100 on TERT-CLPTM1L indicates a poor prognosis for lung cancer in the Chinese Han population.

Upregulation of miR-494 Inhibits Cell Growth and Invasion and Induces Cell Apoptosis by Targeting Cleft Lip and Palate Transmembrane 1-Like in Esophageal Squamous Cell Carcinoma.

Potential target genes of microRNA (miR)-494 have been reported in many types of cancers. However, the role of miR-494 in esophageal squamous cell carcinoma (ESCC) remains unknown. This study focused on the expression and biological function of miR-494 in ESCC. Using bioinformatics analyses, we found that cleft lip and palate transmembrane 1-like (CLPTM1L) was a potential target of miR-494. We performed quantitative real-time (qRT) PCR assays in 37 ESCC tumor tissues to determine the expression of miR-494 and CLPTM1L mRNA, and we analyzed the correlation between both of these factors and clinical characteristics. The cell counting kit-8 and colony formation assays were used to evaluate the effects of miR-494 expression on the proliferation of ESCC cells. The transwell migration assay and flow cytometric apoptosis assay were performed to study the influence of miR-494 on the invasion and apoptosis of ESCC cells. Western blotting, luciferase assays, and CLPTM1L knockdown experiments were used to determine whether CLPTM1L was a target of miR-494. The qRT-PCR assays showed significant downregulation of miR-494 (P < 0.05) and upregulation of CLPTM1L mRNA (P < 0.05), both of which were significantly associated with lymph node metastases (P < 0.05). High expression of miR-494 inhibited cell proliferation and invasion and promoted cell apoptosis (P < 0.05). The results also showed that CLPTM1L was a target of miR-494. These results show that the expression of miR-494, which can regulate cell growth, invasion and apoptosis of ESCC cells by targeting CLPTM1L, is downregulated in ESCC tumor tissues. The miR-494-CLPTM1L pathway could be further exploited to develop a new approach to treat ESCC.

CLPTM1L genetic polymorphisms and interaction with smoking and alcohol drinking in lung cancer risk: a case-control study in the Han population from northwest China.

Genetic variants of cleft lip and palate trans-membrane 1-like (CLPTM1L) genes in the p15.33 region of chromosome 5 were previously identified to influence susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in CLPTM1L genes with lung cancer and explored their potential effects on the relationship between environmental risk factors (smoking, drinking) and lung cancer in a Chinese Han population. We genotyped 9 single nucleotide polymorphisms (SNPs) of CLPTM1L in a case-control study with 228 lung cancer cases and 301 controls from northwest China. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression. We identified that the minor alleles of rs451360, rs402710, and rs31484 in CLPTM1L were associated with a 0.52-fold, 0.76-fold, and 0.70-fold decreased risk of lung cancer in allelic model analysis, respectively. In the genetic model analysis, we found rs402710 and rs401681 were associated with decreased lung cancer risk. Further stratification analysis showed that rs380286 displayed a significantly decreased lung cancer risk (OR=0.65, P=0.041) in the non-drinkers. In addition, Haplotype "GTTATCTGT" was found to be associated with decreased lung cancer risk (OR=0.50, P=0.033). Our results verified that genetic variants of CLPTM1L contribute to lung cancer susceptibility in the northwest Chinese Han population. Additionally, we found that consumption of alcohol may interact with CLPTM1L polymorphisms to contribute to overall lung cancer susceptibility.

Association between CLPTM1L-TERT rs401681 polymorphism and risk of pancreatic cancer: a meta-analysis.

Telomere biology plays a critical and complex role in the initiation and progression of cancer. Several recent studies have provided evidence that rs401681 polymorphisms in intronic region of cleft lip and palate trans-membrane 1-like (CLPTM1L) gene sequence are associated with pancreatic cancer (PC) development, but a comprehensive synopsis is not available. We performed a meta-analysis of 6 case-control studies that included 8,253 pancreatic cancer cases and 37,646 case-free controls. We assessed the strength of the association, using odds ratios (ORs) with 95 % confidence intervals (CIs). Overall, this meta-analysis showed that rs401681 allele T was associated with a significantly increased PC risk (OR = 1.17, 95 % CI = 1.12-1.22, P heterpgeneity = 0.596 and I (2) = 0). Similarly, in the subgroup analysis by ethnicity, a significantly increased risk was found among Asians (OR = 1.15, 95 % CI = 1.07-1.24, P heterpgeneity = 0.297 and I (2) = 8.0 %) and among Caucasian (OR = 1.13, 95 % CI = 1.02-1.26, P heterpgeneity = 0.385 and I (2) = 0). No publication bias was found in the present study. This meta-analysis suggests that T allele of CLPTM1L-telomerase reverse transcriptase rs401681 polymorphism is associated with an increased PC risk, especially among Chinese. Further large and well-designed studies are needed to confirm this association.

Correlation of CLPTM1L polymorphisms with lung cancer susceptibility and response to cisplatin-based chemotherapy in a Chinese Han population.

The implication of genetic factors in predisposition to cancer is a recognized fact. The Cleft lip and palate transmembrane 1-like (CLPTM1L) gene resides in a locus in the chromosome 5p15.33 region that is associated with lung cancer susceptibility and has a role in carcinogenesis. We conducted a case-control study in a Chinese population of 309 pathologically confirmed lung cancer patients and 310 controls to investigate the effect of variant genotypes within the CLPTM1L locus on susceptibility to lung cancer and sensitivity to cisplatin-based chemotherapy. We genotyped nine single nucleotide polymorphisms (SNPs) within the CLPTM1L locus and examined their correlation with lung cancer risk and treatment response using χ (2) and unconditional logistic regression analysis. We identified rs451360 as a novel SNP associated with lung cancer risk in the Chinese Han population. The "T" allele of rs451360 was associated with decreased risk of lung cancer (p = 0.007, odd ratio (OR) = 0.59, 95% confidence interval (CI): 0.40-0.87). Significant multiplicative interactions were observed between gender and polymorphisms of rs402710, the "T/T" genotype of which was associated with decreased lung cancer risk in male patients (p = 0.016, OR = 0.35, 95% CI: 0.17-0.73). CLPTM1L polymorphisms did not affect the tumor sensitivity to cisplatin combination chemotherapy in our study patients. The results of the present study suggest a potential association between CLPTM1L variants and lung cancer risk in the Chinese Han populations.

Genetic polymorphisms of TERT and CLPTM1L, cooking oil fume exposure, and risk of lung cancer: a case-control study in a Chinese non-smoking female population.

Genetic polymorphisms of telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the risks of lung cancer. This study aimed to investigate the association between polymorphisms in TERT and CLPTM1L genes with the risk of lung cancer, as well as the interaction of the polymorphisms and the environmental risk factors in Chinese non-smoking females. A hospital-based case-control study of 524 cases and 524 controls was conducted. Two polymorphisms were determined by Taqman allelic discrimination method. The statistical analyses were performed mostly with SPSS. This study showed that the individuals with the TG or GG genotypes of TERT polymorphism (rs2736100) were at an increased risk for lung cancer compared with those carrying the TT genotype in Chinese non-smoking females [adjusted odds ratios (ORs) were 1.44 and 1.85, 95 % confidence intervals (CIs) were 1.09-1.90 and 1.29-2.65, respectively]. The stratified analysis suggested that increased risks were more pronounced in lung adenocarcinoma (corresponding ORs were 1.71 and 2.30, 95 % CIs were 1.25-2.35 and 1.54-3.43). Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese non-smoking females (adjusted ORs 1.59, 95 % CI 1.13-2.23). However, we did not observe a significant interaction of cooking oil fume and TERT polymorphism on lung cancer among Chinese non-smoking females. TERT polymorphism (rs2736100) might be a genetic susceptibility factor for lung cancer in non-smoking females in China.

Genetic variations in TERT-CLPTM1L genes and risk of lung cancer in a Chinese population.

This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane1-like (CLPTM1L) and lung cancer risk in a Chinese population. We performed a hospital-based case-control study, including 980 lung cancer cases and 1000 cancer-free controls matched for age and sex. Each case and control was interviewed to collect information by well-trained interviewers. A total of 5 ml of venous blood was collected for genotype testing of TERT rs2736098 and CLPTM1L rs401681 using TaqMan methodology. The results revealed that the variant homozygote TERT rs2736098TT was associated with an increased risk of lung cancer (OR=2.017, 95%CI=1.518-2.681), especially lung adenocarcinoma (OR=2.117, 95%CI=1.557-3.043) and small cell carcinoma (OR=1.979, 95%CI: 1.174-3.334), compared with the TERT rs2736098CC genotype. Similar results were observed in non-smokers. The TERT rs2736098 polymorphism might affect the susceptibility to lung cancer in Chinese populations. The associations need to be verified in larger and different populations.

Genetic variant rs401681 at 5p15.33 modifies susceptibility to lung cancer but not esophageal squamous cell carcinoma.

BackgroundThe human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsWe genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case–control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.ResultsLogistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625–0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635–0.972, P = 0.026). Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR = 0.910, 95% CI = 0.734–1.129, P = 0.392; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624–1.290, P = 0.558; CT/TT vs. CC: adjusted OR = 0.908, 95% CI = 0.740–1.114, P = 0.355).ConclusionsOur findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.

Genetic polymorphisms of TERT and CLPTM1L and risk of lung cancer—A case–control study in a Chinese population

Background/objectivesGenetic variants of telomerase reverse transcriptase (TERT) and cleft lip and palate trans-membrane 1 like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the susceptibility to lung cancer. We examined the association of single nucleotide polymorphisms (SNPs) in TERT and CLPTM1L genes with lung cancer and explored their potential modifying effects on the relationship between environmental risk factors and lung cancer in a Chinese population. MethodsWe genotyped rs2736100 (TERT) and rs401681 (CLPTM1L) SNPs in a case–control study with 399 lung cancer cases and 466 controls form Taiyuan, China. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. Potential confounders were controlled for in the adjusted models. ResultsWe found that the GG genotype of TERT was positively associated with lung cancer (OR=1.47, 95% CI: 1.00–2.16). The association was stronger in participants older than 60years, exposed to low indoor air pollution and adenocarcinoma and squamous cell carcinoma (SCC) in recessive model analysis. The GA genotype of CLPTM1L was inversely associated with lung cancer (OR=0.72, 95% CI: 0.54–0.97). The association was stronger in participants 60 years old or younger, males, heavy smokers, exposed to low indoor air pollution and SCC in dominant model analysis. Individuals carrying both TERT and CLPTM1L risk genotypes had higher risk of lung cancer (OR=1.80, 95% CI: 1.15–2.82). Significant interaction was observed between CLPTM1L and indoor air pollution in association with lung cancer. ConclusionsOur results reiterate that genetic variants of TERT and CLPTM1L contribute to lung cancer susceptibility in Chinese population. These associations need to be verified in larger and different populations.

Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk: A Field Synopsis and Meta-Analysis

Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.

Genetic sequence variant (GSV) in TERT-CLPTM1L (5p15.33 locus) and survival in platinum-treated stage-IV non-small cell lung cancer (NSCLC).

1535 Background: Lung cancer is a leading cause of cancer-related mortality in North America. Besides tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether GSVs associated with lung cancer risk are also associated with overall survival (OS) and progress free survival (PFS) in platinum-treated stage-IV NSCLC patients. We chose this subset of patients with lung cancer because they are uniformly treated and followed up at our institute (Princess Margaret Hospital). Methods: A total of 32 candidate GSVs in 21 genes previously reported to be associated with lung cancer risk were genotyped in 188 platinum-treated NSCLC stage-IV patients. Illumina Custom GoldenGate Genotyping Panel was used for the genotyping assay platform. Multivariate Cox proportional hazard models adjusted for the potential clinical prognostic factors were generated for OS and PFS. Results: Median age is 60 yr (range: 31-81); 73% with adenocarcinoma. Median follow-up time is 27 mo; median OS is 16 mo and PFS is 8 mo. The top significant GSV was rs4975616 (g.1315660G&gt;A) in telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) gene on chromosome 5p15.33. The adjusted hazard ratio (aHR) for OS was 0.76 (95% CI: 0.58-0.99; p=0.04) and for PFS aHR was 0.70 (95% CI: 0.55-0.90; p=0.005) for each protective allele, respectively. This GSV has previously been associated with lung cancer risk in genome-wide association study (PMID: 19654303). Conclusions: The TERT-CLPTM1L:rs4975616 GSV is not only a risk factor for lung cancer but also is associated with survival in patients with stage-IV NSCLC treated with platinum based chemotherapy. GSVs may be able to define subsets of patients with different risk and prognosis of NSCLC. Future studies should evaluate whether this GSV is predictive or prognostic.

Abstract 2606: Absence of association between common genetic polymorphisms in the TERT-CLPTM1L locus and breast cancer risk in women of African descent

Abstract Recent genome wide association studies (GWAS) provided evidence that common low-penetrance single nucleotide polymorphisms (SNPs) contribute to breast cancer development. Common SNPs in the TERT (telomerase reverse transcriptase)-CLPTM1L (cleft lip and palate transmembrane 1 like) locus have been reported to be associated with several types of cancer, such as lung cancer/adenocarcinoma, glioma, bladder cancer, prostate cancer, and pancreatic cancer. Researchers also hypothesized that common SNPs in the TERT gene could play a role in breast cancer susceptibility. However, findings are inconsistent, and most studies included Caucasians only. In the present study, we sought to investigate whether common genetic variants in the TERT-CLPTM1L locus could contribute to breast cancer susceptibility in women of African ancestry. A total 2,892 women of African ancestry were participated in the present study, consisting of 1,509 breast cancer cases and 1,383 controls collected from Nigeria, Barbados, and the United States. Eleven SNPs in the TERT-CLPTM1L locus that were previously shown to be associated with cancers were selected and genotyped using the Illumina GoldenGate Genotyping platform, together with 30 ancestry informative markers (AIMs). Test for HWE suggested that the genotypes for all the SNPs were in Hardy-Weinberg proportions and there was no deviation from HWE. We performed unconditional multiple logistic regression to estimate the association between the TERT-CLPTM1L genetic variants and breast cancer risk, adjusting for age, study site, and estimated genetic ancestry. Overall we did not observe any P value &amp;lt; 0.05 after permutation in the analyses of allelic and genotypic models. We also conducted haplotype analysis for a five-SNP LD block, rs4975616-rs3816659-rs402710-rs401681-rs31489 but again failed to obtain significant association in the present study. Our findings do not support an effect of the tested genetic variants in the TERT-CLPTM1L locus on breast cancer susceptibility in women of African ancestry. However, it is worth noting that our current study did not apply a fine-mapping strategy; other genetic variants in LD with previously reported cancer susceptibility polymorphisms might be bona fide causal variants contributing to the risk of breast cancer. Larger independent studies from diverse populations are expected to evaluate the importance of the TERT-CLPTM1L locus in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2606. doi:1538-7445.AM2012-2606