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S. Lam
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MINI 23 - Lung Cancer Risk: Genetic Susceptibility and Airway Biology (ID 135)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:P.E. Postmus, R. Young
- Coordinates: 9/08/2015, 16:45 - 18:15, 401-404
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MINI23.07 - The Airway Field of Injury Reflects Metabolic Changes Associated with the Presence of Lung Squamous Premalignant Lesions (ID 2251)
17:20 - 17:25 | Author(s): S. Lam
- Abstract
Background:
Lung SCC arises in the epithelial layer of the bronchial airways and is preceded by the development of premalignant lesions (PMLs). The molecular events involved in the progression of PMLs to lung SCC are not clearly understood as not all PMLs that develop go on to form carcinoma. Our group is using high-throughput genomic techniques to characterize the process of premalignant progression by examining PMLs and non-lesion areas of individuals with PMLs (“field of injury”) to identify events that lead to the development of SCC. Pathway analysis revealed enrichment oxidative phosphorylation (OXPHOS) /respiratory electron transport among genes up-regulated in the airways of subjects with PMLs. OXPHOS is the most efficient metabolic pathway that generates energy in the form of ATP by utilizing the structures and enzymes of the mitochondria. OXPHOS is often elevated during epithelial tissue repair and is superseded by glycolysis in the development of cancer.
Methods:
mRNA-Seq was conducted on cytologically normal airway epithelium collected from indviduals with (n=50) and without (n=25) PMLs. Linear modeling strategies were used to identify genes altered between subjects with and without PMLs (n=206 out of 13,900, genes at FDR<0.001). Pathway analysis by GSEA revealed enrichment (FDR<0.05) of oxidative phosphorylation (OXPHOS)/respiratory electron transport genes among genes up-regulated in subjects with PMLs. To validate these findings, we examined oxygen consumption rates (OCR) and extracellular acidification rates (ECAR) in primary airway epithelial cells cultures from PMLs and non-lesion areas and cancer cell lines that have high OXPHOS/ moderate glycolytic (H1299), moderate OXPHOS/ high glycolytic (HCC4006) or low OXPHOS/ low glycolytic (H2085) gene expression. In addition, protein expression of genes elevated in the field of injury including, translocase of the outer mitochondrial membrane (TOMM 22) and cytochrome C oxidase (COX-IV) were measured in FFPE sections of human PMLs and PMLs from the N-nitroso-tris-chloroethylurea (NTCU) mouse model of lung SCC.
Results:
OCR and ECAR values in the lung cancer cell lines were consistent with gene expression patterns. Perturbations of OXPHOS resulted in 3 fold (H1299) and 2 fold (HCC4006) higher OCR vales than those in H2085 cells (p<0.05) reflecting higher OXPHOS activity. Whereas the ECAR values were 2.5 fold (HCC4006) and 1.5 fold (H1299) higher than those in H2085 cells (p<0.05), reflecting higher glycolytic metabolism. The OCR and ECAR patterns in the primary premalignant cultures also supported the computational findings in the field of injury of PMLs. The baseline OCR/ECAR values were 1.5 fold higher in the cultures from PMLs compared to non-lesions controls (p<0.001). Additionally the OCR and ECAR values were elevated in response to perturbations in OXPHOS in the PMLs compared to controls. Protein levels of TOMM 22, and COX-IV were found to be elevated in dysplastic lesions compared to controls.
Conclusion:
Together these data suggest that metabolism-associated gene expression is correlated with cellular metabolism and there is an increase in OXPHOS associated with the development of PMLs. Furthermore, there is potential that therapeutically increasing or maintaining OXPHOS in premalignant lesions or the field of injury may be a mechanism of prevention for lung cancer.
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MINI 34 - RNA and miRNA (ID 162)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:C. Mascaux, L.(. Wang
- Coordinates: 9/09/2015, 18:30 - 20:00, 205+207
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MINI34.12 - Oncofetal miRNA Expression Inactivates Nuclear Factor I/B, a Critical Regulator of Lung Development and Lung Adenocarcinoma Pathogenesis (ID 3023)
19:35 - 19:40 | Author(s): S. Lam
- Abstract
Background:
Fetal development shares many biological similarities with tumourigenesis such as high rates of cell proliferation and vasculature restructuring. Particularly in the lung, a number of genes and pathways involved in the development of this organ play important roles in the malignant transformation of adult lung cells. Despite these biological similarities, there is a paucity of information regarding how specific molecular regulators involved in fetal lung development become oncogenes in lung cancer. This is the case for micro RNAs (miRNAs), which have a pivotal role in regulating gene expression during organ development and tumourigenesis. Therefore, a better understanding of the human fetal lung miRNA-transcriptome has the potential to reveal key players in lung cancer development and progression.
Methods:
131 pairs of non-small cell lung cancer (NSCLC) tumour and adjacent non-malignant lung tissues and 15 human fetal lung tissue samples were profiled by miRNA-sequencing. Mann–Whitney U tests were performed with Benjamini-Hochberg multiple testing corrections to identify miRNAs abundantly expressed in fetal and tumour tissues but scarce in non-malignant adult lung (i.e. oncofetal miRNAs). To investigate protein-coding genes controlled by the oncofetal miRNAs identified, miRDIP was applied followed by gene reporter luciferase assay experiments. The assessment of associations between patient survival and mRNA expression of selected genes targeted by the oncofetal miRNAs was evaluated in multiple NSCLC cohorts (>1,400 tumour cases). To validate the protein expression of the most prominent gene regulated by the oncofetal miRNAs identified, immunohistochemical (IHC) analysis was performed on a lung adenocarcinoma (LUAD) tissue microarray (TMA).
Results:
We describe for the first time a comprehensive, unbiased characterization of miRNA expression in human fetal lung tissue by miRNA sequencing. Through comparison to a large cohort of NSCLC, we identified numerous miRNAs that recapitulate their fetal expression patterns in lung cancer. Strikingly, assessment of the genes potentially regulated by these oncofetal miRNAs led us to identify Nuclear Factor I/B (NFIB), a transcription factor essential for lung development, as being frequently targeted by oncofetal miRNAs. Concordantly, analysis of NFIB expression using RNA-sequencing data for multiple NSCLC cohorts revealed its frequent underexpression in tumours (>60%). Remarkably, low expression of NFIB was significantly associated with poorer survival in LUAD patients but not in squamous cell carcinoma patients, consistent with the functional role of NFIB in distal lung cell differentiation (i.e. cells that are the precursors of LUAD). Furthermore, an NFIB-related gene signature was identified in LUAD tumours and included several well-known lung differentiation markers (TTF-1, ABCA3, GPR116, SFTPB). Finally, the underexpression of NFIB protein was validated on a LUAD TMA, which also revealed that tumours presenting lower levels of this transcription factor are associated with higher grade, biologically more aggressive LUAD (invasive mucinous, micropapillary and solid subtypes).
Conclusion:
This work has revealed a prominent mechanism for the downregulation of a crucial gene for lung development, which we found to be associated with aggressive phenotypes of LUAD and consequently, poor patient survival. Elucidating the specific role of NFIB in lung cancer biology will likely lead to the identification of targetable tumour vulnerabilities.
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MINI 36 - Imaging and Diagnostic Workup (ID 163)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 2
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MINI36.04 - Automated Measurement of Malignancy Risk of Lung Nodule Detected by Screening Computed Tomography (ID 1737)
18:45 - 18:50 | Author(s): S. Lam
- Abstract
- Presentation
Background:
We have previously reported a practical predictive tool that accurately estimates the probability of malignancy for lung nodules detected at baseline screening LDCT (New Engl J Med. 2013;369:908-17). Manual measurement of nodule dimensions and generation of malignancy risk scores is time consuming and subjected to intra- and inter-observer variability. The goal of this study is to prepare a nodule malignancy risk prediction model based on automated computer generated nodule data and compare it to an established model based on radiologists’ generated data.
Methods:
Using the same published PanCan dataset (New Engl J Med. 2013;369:908-17) with the number of lung cancers updated, we prepared a logistic regression model predicting lung cancer using computer-generated imaging data from the CIRRUS Lung Screening software (Diagnostic Imaging Analysis Group, Nijmegen, The Netherlands). Ninety-one of the 2,537 baseline (first) scans were not available or could not be processed by CIRRUS. The remaining 2,446 scans were first annotated by the CIRRUS software. A human non-radiologist reader then accepted/rejected the annotated marks and manually searched the LDCT for nodules missed by CIRRUS or the study radiologist. New nodules found that were not recorded by the study radiologist were reviewed by a subspecialty trained chest radiologist with 14 years experience in lung cancer screening (JM). Nodule morphometric measurements (maximum and mean diameter, volume, mass, density) and total nodule count per scan irrespective of size were automatically generated by the CIRRUS software. The nodule type (nonsolid, part-solid, or solid), nodule description (lobulated, spiculated or well defined) and nodule location (upper versus middle or lower lobe) were manually entered. The variables were evaluated in models as untransformed and natural log transformed variables. Nonlinear relationships with lung cancer were also evaluated. Socio-demographic and clinical history predictors were not included in the model.
Results:
Radiologists evaluation identified 8,570 pulmonary nodules of any size in 2063 individuals - 124 nodules in 119 individuals were diagnosed as cancer in follow-up. Based on CIRRUS software annotated marks that were accepted by a human reader, computer analysis identified 11,520 pulmonary nodules in 2174 individuals - 121 nodules in 115 individuals were diagnosed as cancer in follow-up. Thirty-six percent of new nodules found by CIRRUS and/or second human reader were ≥4 mm (mean±SD, 5.9± 3.5 mm). Both the computer generated imaging data model (Model-CIRRUS) and the radiologist generated data model (Model-RAD) demonstrated excellent discrimination and calibration. Their predictive performances were also similar. Comparing Model-CAD to Model-RAD, the AUCs were 0.9537 versus 0.9541, the 90[th] percentile absolute errors were 0.0008 versus 0.0007, and the Brier scores were 0.0093 versus 0.0137. Mean nodule diameter is a better risk predictor than maximum nodule diameter, nodule density or mass.
Conclusion:
The predictive performances of computer and radiologist generated data models were similar. The model can be integrated to the CIRRUS Lung Screening software to automatically generate a nodule malignancy risk score to facilitate nodule management recommendation. Supported by the Terry Fox Research Institute, The Canadian Partnership Against Cancer and the BC Cancer Foundation on behalf of the Pan-Canadian Early Detection of Lung Cancer Study Group.
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MINI36.05 - Computer Vision Tool and Technician as First Reader of Lung Cancer Screening CT (ID 1702)
18:50 - 18:55 | Author(s): S. Lam
- Abstract
- Presentation
Background:
The recommendation by the US Preventive Services Task Force to screen high-risk smokers with low-dose computed tomography (LDCT) and the recent decision by the Centers for Medicare and Medicaid Services to fund LDCT screening under the Medicare program mean that LDCT screening will be implemented at the population level in the US and likely in other countries. With the large volume of scans that will be generated, accurate and efficient interpretation of LDCT images is key to providing a cost-effective implementation of LDCT screening to the large at risk population. Objective To evaluate an alternative workflow to identify and triage abnormal LDCT scans in which a technician assisted by Computer Vision (CV) software acts as first reader with the aim to reduce workload, improve speed, consistency and quality of interpretation of screening LDCT scans.
Methods:
A test dataset of baseline Pan-Canadian Early Detection of Lung Cancer Study LDCT scans (New Engl J Med. 2013;369:908-17) was used. This included: 136 scans with lung cancers, 556 scans with benign nodules and 136 scans without nodules. The scans were randomly assigned for analysis by the CV software (CIRRUS Lung Screening, Diagnostic Imaging Analysis Group, Nijmegen, The Netherlands). The annotated scans were then reviewed by a technician without knowledge of the diagnosis. The scans were classified by the technician as either normal (no nodules or benign nodules only, potentially not requiring radiologist review) or abnormal (suspicious of malignancy or other abnormality requiring radiologist review). The results were compared with the Pan-Can Study radiologists. Nodules found by CIRRUS but not by the radiologist were reviewed by a subspecialty trained chest radiologist with 14 years experience in lung cancer screening (JM).
Results:
The overall sensitivity and specificity of the technician to identify an abnormal scan were: 97.7% (95% CI: 96.3 - 98.7) and 98.0% (95% CI: 89.5 - 99.7) respectively. The technician correctly identified all the scans with malignant nodules. The time taken by the technician to read a scan was 208±120 sec.
Conclusion:
A technician assisted by CV software can categorize accurately abnormal scans for review by a radiologist. Pre-screening by a technician and CV software is a promising strategy for reducing workload, improving the speed, consistency and quality of scan interpretation of screening chest CTs. Supported by the Terry Fox Research Institute, The Canadian Partnership Against Cancer and the BC Cancer Foundation on behalf of the Pan-Canadian Early Detection of Lung Cancer Study Group.
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MS 14 - Chemo Prevention Clinical Trials (ID 32)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Prevention and Tobacco Control
- Presentations: 1
- Moderators:Y.E. Miller, P.E. Postmus
- Coordinates: 9/08/2015, 14:15 - 15:45, 401-404
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MS14.02 - Clinical Trials: Who Are the Proper Cohorts and How Do You Recruit Subjects? (ID 1909)
14:40 - 15:00 | Author(s): S. Lam
- Abstract
- Presentation
Abstract:
Although chemoprevention as a means of reducing cancer incidence has been successful for basal cell carcinoma of skin, breast, and prostate cancer, after three decades of research, none of the phase III trials with agents such as Beta-carotene, retinol, 13-cis-retinoic acid, alpha-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium have demonstrated beneficial and reproducible results in preventing lung cancer, likely due to the complexity of genomic alterations in lung cancer (1). Intermediate endpoint biomarkers such as bronchial metaplasia or dysplasia have been used in Phase II trials (2). Studies on the natural history of pre-neoplastic lesions in the central airways showed that patients with high-grade dysplasia or carcinoma in-situ are more likely to develop invasive cancer at the same or another site in the lungs than those with low grade lesions. However, pre-invasive bronchial lesions may be more of a marker of lung cancer risk because more cancers developed from a separate site in the same individual than progression from an initially biopsied dysplastic site and a significant proportion of the cancers are found by CT rather than by bronchoscopy (3,4). The advantage of using bronchial metaplasia/dysplasia for phase II chemoprevention trials is that these lesions can be localized and biopsied using white light and autofluorescence bronchoscopy for histopathology confirmation. However, with a steady decline in the prevalence of centrally located squamous cell carcinomas and a shift to adenocarcinomas which are usually located in the peripheral lung beyond the range of sampling by standard flexible bronchoscopes, it has become increasingly difficult to enrol participants with bronchial dysplasia for clinical trial. With the implementation of low dose computed tomography for screening of lung cancer, alternative intermediate endpoint biomarkers, such as CT detected non-calcified lung nodules are being investigated for phase II lung cancer chemoprevention trials (5). The limitations of using CT-detected lung nodules as an intermediate endpoint are the lack of confirmation of the underlying pathology and variable growth behaviour of sub-solid nodules especially non-solid nodules (6,7). Without confirmation of the pathology (atypical adenomatous hyperplasia versus adenocarcinoma in-situ versus minimally invasive or invasive adenocarcinoma), when a nodule is first seen, volume doubling time measurement is meaningless to determine malignant behaviour. Endoscopic optical imaging tools such as combined auto-fluorescence-optical coherence tomography (8) are promising methods to localize and characterize small peripheral lung lesions for tissue or liquid biopsy for pathological diagnosis and molecular characterization (Example shown in Figure 1). The availability of accurate lung cancer risk prediction models such as the one developed by Tammemagi and co-workers (9 ) opens the possibility of using lung cancer as the endpoint for chemoprevention trials in high risk ever smokers instead of intermediate endpoint biomarkers to test chemopreventive agents that have sound biological basis. Prospective evaluation of a prototype PLCOm2012 lung cancer risk prediction model in the Pan-Canadian early Detection of Lung Cancer Study showed that a 3 years lung cancer risk of ≥2% can reliably identify a sufficient number of ever smokers who will develop lung cancer within 3 years to make it feasible to use lung cancer incidence as the endpoint for chemoprevention trials with a sample size of approximately 2500 participants. The sample size can be significantly reduced by using a nodule malignancy risk prediction model (10). There is great potential to partner with lung cancer screening programs for developing and testing biologically rationalized agents for chemoprevention clinical trials within this framework, which may lead to their eventual implementation in screening programs to improve patient outcomes. Figure 1. Autofluorescence –Optical Coherence Tomography images of a CT-detected lung nodule showing the invasive and lepidic components of the adenocarcinoma confirmed by transbronchial lung biopsy. Figure 1 Supported by the Terry Fox Research Institute, Canadian Partnership Against Cancer, the Canadian Institute of Health Research and Lung Cancer Canada. References 1. Szabo E, Mao JT, Lam S, Reid ME, & Keith RL (2013) Chemoprevention of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 143(5 Suppl):e40S-60S. 2. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, et al. Oral iloprost improves endobronchial dysplasia in former smokers. Cancer Prev Res (Phila). 2011;4:793-802. 3. Ishizumi T, McWilliams A, MacAulay C, Gazdar A, Lam S. Natural history of bronchial preinvasive lesions. Cancer Metastasis Rev. 2010;29:5-14. 4. Jeremy George P, Banerjee AK, Read CA, O'Sullivan C, Falzon M, Pezzella F, et al. Surveillance for the detection of early lung cancer in patients with bronchial dysplasia. Thorax. 2007;62:43-50 5. Veronesi G, Szabo E, Decensi A, Guerrieri-Gonzaga A, et al. Randomized Phase II trial of inhaled budesonide versus placebo in high-risk individuals with CT screen-detected lung nodules. Cancer Prev Res 2011; 1:34-42. 6. Massion PP. Walker RC. Indeterminate pulmonary nodules: Risk for having or for developing lung cancer? Cancer Prev Res 2014;7:1173-1178. 7. Pinsky PF, Nath PH, Gierada DS, Sonavane S, Szabo E. Short- and long-term lung cancer risk associated with noncalcified nodules observed on low-dose CT. Cancer Prev Res (Phila). 2014;7:1179-85. 8. Pahlevaninezhad H, Lee AM, Shaipanich T, Raizada R, Cahill L, Hohert G, Yang VX, Lam S, MacAulay C, Lane P. A high-efficiency fiber-based imaging system for co-registered autofluorescence and optical coherence tomography. Biomed Opt Express. 2014 Aug 6;5(9):2978-87. doi: 10.1364/BOE.5.002978. eCollection 2014 Sep 1. 9. Tammemagi MC, et al. (2013) Selection criteria for lung-cancer screening. The New England journal of medicine 368(8):728-736. 10. Tammemagi MC, Lam S. Screening for lung cancer using low dose computed tomography. BMJ. 2014 May 27;348:g2253. doi: 10.1136/bmj.g2253. Review.
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ORAL 09 - CT Screening - New Data and Risk Assessment (ID 95)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J. Mulshine, J.K. Field
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL09.07 - Economic Evidence for the Use of Risk-Selection and Risk-Stratification for Lung Cancer Screening Programs (ID 2928)
11:39 - 11:50 | Author(s): S. Lam
- Abstract
- Presentation
Background:
Screening for lung cancer according to age and smoking history alone could cost billions of dollars of public health expenditure due to the high incidence of potential participants. Risk-adapted lung cancer screening strategies such as participant selection (based on published risk prediction models such as the PLCOm2012 model) and malignancy risk based screening protocols may reduce program costs while improving outcomes among current and former smokers at risk of developing the disease. The Pan-Canadian Early Detection of Lung Cancer Study (PanCan) was designed with the objective of providing economic evidence for an affordable lung cancer-screening program in Canada.
Methods:
Data for 2537 screening participants in the PanCan study (median follow-up time of 4 years) and 25,914 eligible participants from the NLST-CXR arm were included in the analysis. There was adequate power and follow-up to inform the transition probabilities in model and provide the distribution to test all model parameters simultaneously in a probabilistic sensitivity analysis. The cost and health utility inputs are from patient-level trial data with defined ranges of certainty.
Results:
Our results show that risk selection using the PanCan risk prediction model could reduce the need to screen 21,022 (81%) of the NLST population if risk prediction were applied. If risk prediction were applied to Canadians who met the NLST criteria, 2 year program costs could be reduced by 400 million dollars and nearly half a million people could be spared the potential harms from screening that is not likely to result in a Cancer diagnosis. With the economic evidence from the PanCan and NLST trials, we report our initial cost-effectiveness results and will show, for the first time, a definitive description of the uncertainty surrounding our cost-effectiveness ratios.
Conclusion:
Using a model loaded with patient-level screening data has enabled us to predict the likelihood that risk-adapted screening will fall below most commonly referenced thresholds of acceptability for cancer interventions. The initial results and characterization of the parameters affecting cost-effectiveness will be presented. [*]on behalf of the PanCan study team The panCan study is sponsored by the Terry Fox Research Institute and the Canadian Partnership against Cancer, ARCC is funded by the CCSRI The authors thank the National Cancer Institute for access to NCI’s data collected by the National Lung Screening Trial. The statements contained herein are solely those of the authors and do not represent or imply concurrence or endorsement by NCI
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ORAL 23 - Prevention and Cancer Risk (ID 121)
- Event: WCLC 2015
- Type: Oral Session
- Track: Prevention and Tobacco Control
- Presentations: 1
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ORAL23.01 - A Randomized Phase IIb Trial of Myo-Inositol in Smokers with Bronchial Dysplasia (ID 856)
10:45 - 10:56 | Author(s): S. Lam
- Abstract
- Presentation
Background:
Previous preclinical studies and a phase I clinical trial suggested myo-inositol may be a safe and effective lung cancer chemopreventive agent. We conducted a randomized, double blind, placebo-controlled, phase IIb study to determine the chemopreventive effects of myo-inositol in smokers with bronchial dysplasia.
Methods:
Smokers with ≥1 site of dysplasia identified by autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive oral placebo or myo-inositol, 9 g once/day for two weeks, and then twice/day for 6 months. The primary endpoint was change in dysplasia rate after six months of intervention on a per participant basis. Other trial endpoints reported herein include Ki-67 labeling index and pro-inflammatory, oxidant/anti-oxidant biomarker levels in blood and bronchoalveolar lavage fluid (BAL).
Results:
Seventy four (n=38 myo-inositol, n=36 placebo) participants with a baseline and 6-month bronchoscopy were included in all efficacy analyses. The complete response and the progressive disease rates were 26.3% versus 13.9% and 47.4% versus 33.3%, respectively, in the myo-inositol and placebo arms (p=0.76). The mean percent change in Ki67 labeling index in bronchial biopsies with dysplasia was -22.8% and -6.2%, respectively, in the myo-inositol and placebo arms (p=0.34). Compared with placebo, myo-inositol intervention significantly reduced IL-6 levels in BAL over 6 months (p=0.03) and had borderline significant effects on BAL myeloperoxidase (p= 0.06) level.
Conclusion:
The heterogeneous response to myo-inositol suggests a targeted therapy approach based on molecular alterations is needed in future clinical trials to determine the efficacy of myo-inositol as a chemopreventive agent.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-074 - ITPKA Expression in Lung and Other Cancers, Regulated via Gene Body Methylation, Functions as an Oncogene (ID 1026)
09:30 - 09:30 | Author(s): S. Lam
- Abstract
Background:
Lung cancer is the leading cause of cancer mortality and accounts for 1.6 million deaths annually in the world. Lung cancers may be classified into non-small cell (NSCLC) and small cell (SCLC) lung cancers, which individually account for approximately 85% and 15%, respectively, of lung cancer cases. Despite recent advances in cancer therapy, the overall 5-year survival rate of lung cancer remains low. There remains an urgent need for discovery of novel approaches for early diagnosis and therapy. Inositol-trisphosphate 3-kinase A (ITPKA) regulates inositol phosphate metabolism and calcium signaling by phosphorylation of the second messenger inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) to inositol-1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) (1). ITPKA has a very limited tissue expression, mainly in brain and testis. ITPKA, previously known as a neuron-specific F-actin bundling protein, has recently been shown to be overexpressed in lung adenocarcinoma and associated with increased metastatic potential (2). However, our understanding of the role and regulation of ITPKA in cancers is limited. Reference: 1. Shears SB. How versatile are inositol phosphate kinases? The Biochemical journal. 2004; 377:265-80. 2. Windhorst S, Kalinina T, Schmid K, Blechner C, Kriebitzsch N, Hinsch R, et al. Functional role of inositol-1,4,5-trisphosphate-3-kinase-A for motility of malignant transformed cells. International journal of cancer Journal international du cancer. 2011;129:1300-9.
Methods:
To identify potential oncogenes that are involved in the pathogenesis of lung cancer, cDNA microarray analysis was performed to search for up-regulated genes in primary lung adenocarcinomas. Inositol-trisphosphate 3-kinase A (ITPKA) was found to be overexpressed in lung ADC.
Results:
Using gain-of-function and loss-of-function approaches, we demonstrated that ITPKA contributes to cancer development. We also showed that methylation level in the ITPKA gene body is highly tumor-specific, and is positively correlated with its expression. Furthermore, DNMT3B-mediated methylation of the CpG island in ITPKA gene body regulates its expression via modulation of the binding of transcription activator SP1 to the ITPKA promoter. ITPKA gene body methylation first appeared at the in situ carcinoma stage and progressively increased during the multistage pathogenesis of lung carcinoma. Figure 1
Conclusion:
Altogether, deregulation of ITPKA may promote oncogenic transformation and function as a universal or near universal hallmark of malignancy. A novel regulatory mechanism of oncogene expression was demonstrated via gene body methylation which manipulates the binding of transcriptional factor(s) to its promoter and controls gene expression.
