GATA2 is Epigenetically Repressed in Human and Mouse Lung Tumors and Is Not Requisite for Survival of KRAS Mutant Lung Cancer

Tessema, Mathewos; Yingling, Christin M.; Snider, Amanda M.; Do, Kieu; Juri, Daniel E.; Picchi, Maria A.; Zhang, Xiequn; Liu, Yushi; Leng, Shuguang; Tellez, Carmen S.; Belinsky, Steven A.

doi:10.1097/jto.0000000000000165

Cited by 27 publications

(18 citation statements)

References 44 publications

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“…Epigenetic regulation of these genes has been strongly implicated earlier in lung cancer. [37][38][39][40][41] However, methylation in genes such as CDKN2A did not cross the thresholds in our study possibly because differing methylation patterns in CDKN2A has been reported in different lung cancer histological types. 42 We detected smoking-related methylation changes in several CpGs or genes that have earlier been reported to associate with smoking.…”

Section: Discussionmentioning

confidence: 66%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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Previous studies have revealed a robust association between exposure to asbestos and human lung cancer. Accumulating evidence has highlighted the role of epigenome deregulation in the mechanism of carcinogen-induced malignancies. We examined the impact of asbestos on DNA methylation. Our genome-wide studies (using Illumina HumanMethylation450K BeadChip) of lung cancer tissue and paired normal lung from 28 asbestos-exposed or non-exposed patients, mostly smokers, revealed distinctive DNA methylation changes. We identified a number of differentially methylated regions (DMR) and differentially variable, differentially methylated CpGs (DVMC), with individual CpGs further validated by pyrosequencing in an independent series of 91 non-small cell lung cancer and paired normal lung. We discovered and validated BEND4, ZSCAN31 and GPR135 as significantly hypermethylated in lung cancer. DMRs in genes such as RARB (FDR 1.1 3 10 219 , mean change in beta [D] 20.09), GPR135 (FDR 1.87 3 10 28 , mean D 20.09) and TPO (FDR 8.58 3 10 25 , mean D 20.11), and DVMCs in NPTN, NRG2, GLT25D2 and TRPC3 (all with p <0.05, t-test) were significantly associated with asbestos exposure status in exposed versus non-exposed lung tumors. Hypomethylation was characteristic to DVMCs in lung cancer tissue from asbestos-exposed subjects. When DVMCs related to asbestos or smoking were analyzed, 96% of the elements were unique to either of the exposures, consistent with the concept that the methylation changes in tumors may be specific for risk factors. In conclusion, we identified novel DNA methylation changes associated with lung tumors and asbestos exposure, suggesting that changes may be present in causal pathway from asbestos exposure to lung cancer.Lung cancer is the leading cause of cancer-related deaths, accounting for around every fifth global cancer death. 1 While tobacco smoking remains the principal risk factor for lung carcinogenesis, exposure to asbestos, a group of naturally occurring fibrous silicate minerals with multiple commercial applications, is the most important occupational risk factor for lung cancer. 2 Asbestos exposure causes 6 to 23% of all male lung cancers (estimates depending on the exposure and population), and >107,000 deaths annually from asbestosrelated diseases. 3,4 All forms of asbestos are carcinogenic to

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Section: Discussionmentioning

confidence: 66%

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Kettunen

Hernandez-Vargas

Cros

et al. 2017

Intl Journal of Cancer

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“…S2B), suggest DNA methylation is likely involved in miR-486-5p repression. However, our HM450K-based quantitative methylation data [34,35] revealed that the ~5kb region containing miR-486 is strongly methylated in all samples including DNLT (Fig. S2C).…”

Section: Resultsmentioning

confidence: 99%

“…The methylation levels of ANK1B and ANK1E promoters in lung cancer were also quantified using our previous HM450K data [34,35]. A total of 18 HM450K probes interrogated the methylation levels of CpGs across the ANK1B and ANK1E promoters in NHBEC, DNLT (n=24), lung tumors (n=64), and Calu6.…”

Section: Resultsmentioning

confidence: 99%

“…Quantitative methylation data for ANK1 including its promoter CpG islands and the miR-486 containing last intron was obtained from our recent HumanMethylation450 beadchip (HM450K) analysis of lung tumor-normal pairs and cell lines [34,35]. The publicly available HM450K data for 809 NSCLC cases from TCGA was used for independent validation of results.…”

Section: Methodsmentioning

confidence: 99%

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ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

et al. 2017

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The intragenic tumor-suppressor microRNA miR-486-5p is often down-regulated in non-small cell lung cancer (NSCLC) but the mechanism is unclear. This study investigated epigenetic co-regulation of miR-486-5p and its host gene ANK1. MiR-486-5p expression in lung tumors and cell lines was significantly reduced compared to normal lung (p<0.001) and is strongly correlated with ANK1 expression. In vitro, siRNA-mediated ANK1 knockdown in NSCLC cells also reduced miR-486-5p while the DNA methylation inhibitor 5-aza-2′-deoxycytidine induced expression of both. ANK1 promoter CpG island was unmethylated in normal lung but methylated in 45% (118/262) lung tumors and 55% (17/31) NSCLC cell lines. After adjustment for tumor histology and smoking, methylation was significantly more prevalent in adenocarcinoma (101/200, 51%) compared to squamous cell carcinoma (17/62, 27%), p<0.001; HR=3.513 (CI: 1.818–6.788); and in smokers (73/128, 57%) than never-smokers (28/72, 39%), p=0.014; HR=2.086 (CI: 1.157–3.759). These results were independently validated using quantitative methylation data for 809 NSCLC cases from The Cancer Genome Atlas project. Together, our data indicate that aberrant ANK1 methylation is highly prevalent in lung cancer, discriminate tumors by histology and patients’ smoking history, and contributes to miR-486-5p repression.

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“…While a multitude of studies have sought to define KRAS synthetic lethal genes (Costa-Cabral et al, 2016;Kim et al, 2013Kim et al, , 2016Luo et al, 2009;Scholl et al, 2009;Steckel et al, 2012), they have been notable for the fact that they hardly overlap, which has been attributed to the use of different cell lines and screening libraries that may suffer from off-target effects and partial knockdowns (Downward, 2015). As a result, many of the published synthetic lethal genes that have been explored independently have failed to reproduce (Fröhling and Scholl, 2011;Tessema et al, 2014). While a meta-analysis of published synthetic lethals could be an effective way to identify more robust candidates, a systematic integration and re-testing has not yet been performed (Christodoulou et al, 2017;Downward, 2015).…”

Section: Introductionmentioning

confidence: 99%

Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

Ku¹,

Kongara²,

Hu³

et al. 2019

Preprint

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Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. Using KRAS as a model, we identified that published synthetic lethal screens significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks identified synthetic lethal candidates that were more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes were strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identified numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework. STATEMENT OF SIGNIFICANCESynthetic lethal screens have the power to identify new targets in cancer, although have thus far come up short of expectation. We use computational and experimental approaches to delineate principles for identifying robust synthetic lethal targets that could aid in the development of effective new therapeutic strategies for genetically defined cancers.

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GATA2 is Epigenetically Repressed in Human and Mouse Lung Tumors and Is Not Requisite for Survival of KRAS Mutant Lung Cancer

Cited by 27 publications

References 44 publications

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

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