<i>TFAP2E–DKK4</i>and Chemoresistance in Colorectal Cancer

Ebert, Matthias; Tänzer, Marc; Balluff, Benjamin; Burgermeister, Elke; Kretzschmar, A.; Hughes, David J.; Tetzner, Reimo; Lofton–Day, Catherine; Rosenberg, Robert D.; Reinacher‐Schick, Anke; Schulmann, Karsten; Tannapfel, Andrea; Hofheinz, Ralf; Röcken, Christoph; Keller, Gisela; Langer, Rupert; Specht, Katja; Porschen, Rainer; Stöhlmacher-Williams, Jan; Schuster, Tibor; Ströbel, Philipp; Schmid, Roland M.

doi:10.1056/nejmoa1009473

Cited by 165 publications

(159 citation statements)

References 25 publications

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“…[3][4][5][6] Therefore, the in-depth study of the cancer DNA-methylome holds promise to provide important clues as to which genes and biological networks are affected at tumour initiation and progression. Furthermore, it will provide clues as to which genes are epigenetically affected during escape from therapeutic cytotoxicity.…”

mentioning

confidence: 99%

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Ruijter

Hoon

Slaats

et al. 2015

Laboratory Investigation

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Current genome-wide methods to detect DNA-methylation in healthy and diseased tissue require high-quality DNA from fresh-frozen (FF) samples. However, well-annotated clinical samples are mostly available as formalin-fixed, paraffinembedded (FFPE) tissues containing poor-quality DNA. To overcome this limitation, we here aimed to evaluate a DNA restoration protocol for usage with the genome-wide Infinium HumanMethylation450 BeadChip assay (HM-450K). Sixty-six DNA samples from normal colon (n = 9) and breast cancer (n = 11) were interrogated separately using HM-450K. Analyses included matched FF/FFPE samples and technical duplicates. FFPE DNA was processed with (FFPEr) or without a DNA restoration protocol (Illumina). Differentially methylated genes were finally validated in 24 additional FFPE tissues using nested methylation-specific PCR (MSP). In summary, β-values correlation between FFPEr duplicates was high (ρ = 0.9927 (s.d. ± 0.0015)). Matched FF/FFPEr correlation was also high (ρ = 0.9590 (s.d. ± 0.0184)) compared with matched FF/FFPE (ρ = 0.8051 (s.d. ± 0.1028). Probe detection rate in FFPEr samples (98.37%, s.d. ± 0.66) was comparable to FF samples (99.98%, s.d. ± 0.019) and substantially lower in FFPE samples (82.31%, s.d. ± 18.65). Assay robustness was not decreased by sample archival age up to 10 years. We could also demonstrate no decrease in assay robustness when using 100 ng of DNA input only. Four out of the five selected differentially methylated genes could be validated by MSP. The gene failing validation by PCR showed high variation of CpG β-values in primer-binding sites. In conclusion, by using the FFPE DNA restoration protocol, HM-450K assays provide robust, accurate and reproducible results with FFPE tissue-derived DNA, which are comparable to those obtained with FF tissue. Most importantly, differentially methylated genes can be validated using more sensitive techniques, such as nested MSP, altogether providing an epigenomics platform for molecular pathological epidemiology research on archived samples with limited tissue amount. Epigenomic changes are recognised as important factors in tumour initiation, growth and progression. Global and local DNA-methylation patterns are frequently altered in cancer cells, resulting in genomic instability and diminished or elevated expression of tumour-suppressor genes or oncogenes, respectively, driving malignant transformation, growth promotion and metastasis (reviewed in Jones and Baylin 1 and Petronis 2 ). In the clinical setting, cancer-specific DNA-methylation changes are increasingly evaluated as biomarkers for early detection, staging or patient prognosis.In addition, a role for DNA-methylation changes in mediating either cancer drug resistance or drug sensitivity has been hypothesised and verified. [3][4][5][6] Therefore, the in-depth study of the cancer DNA-methylome holds promise to provide important clues as to which genes and biological networks are affected at tumour initiation and progression. Furthermore, it will provide clues as to which g...

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mentioning

confidence: 99%

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Ruijter

Hoon

Slaats

et al. 2015

Laboratory Investigation

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“…Although these findings indicate that TFAP2E is a potent tumor suppressor, it remains elusive how TFAP2E could regulate the expression of cancer-related genes. It has been described that TFAP2E exerts its tumor suppressive function through the downregulation of Dickkopf WNT signaling pathway inhibitor 4 (DKK4) in CRC (11). However, we were unable to detect DKK4 expression in NB1 cells under our experimental conditions (data not shown).…”

Section: Discussionmentioning

confidence: 55%

“…Recently, it has been reported that hypermethylation of TFAP2E genome locus and lower expression of its transcript are associated with unfavorable outcome and non-responsiveness to chemotherapy in colorectal cancer and gastric cancer (11,12). Analysis of the public database revealed that a lower expression of TFAP2E is also related to a shorter survival of neuroblastoma patients.…”

Section: Discussionmentioning

confidence: 99%

“…Intriguingly, aberrant methylation of TFAP2E genomic locus and/or its expression is associated with prognostic outcome or drug resistance in certain human tumors. Indeed, hypermethylation and lower expression levels of TFAP2E have been shown to correlate with resistance to fluorouracil in patients with colon cancer (11). In gastric cancer, hypermethylation and lower expression levels of TFAP2E were much more frequently observed in tumors with lower differentiation grades (12).…”

Section: Introductionmentioning

confidence: 99%

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Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells

et al. 2017

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Abstract. Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system and accounts for approximately 15% of all pediatric cancer-related deaths. To newly identify gene(s) implicated in the progression of neuroblastoma, we investigated aberrantly methylated genomic regions in mouse skin tumors. Previously, we reported that TFAP2E, a member of activator protein-2 transcription factor family, is highly methylated within its intron and its expression is strongly suppressed in mouse skin tumors compared with the normal skin. In the present study, we analyzed public data of neuroblastoma patients and found that lower expression levels of TFAP2E are significantly associated with a shorter survival. The data indicate that TFAP2E acts as a tumor suppressor of neuroblastoma. Consistent with this notion, TFAP2E-depleted neuroblastoma NB1 and NB9 cells displayed a substantial resistance to DNA damage arising from adriamycin (ADR), cisplatin (CDDP) and ionizing radiation (IR). Silencing of TFAP2E caused a reduced ADR-induced proteolytic cleavage of caspase-3 and PARP. Of note, compared with the untransfected control cells, ADR-mediated stimulation of CDK inhibitor p21 WAF1 was markedly upregulated in TFAP2E-knocked down cells. Therefore, our present findings strongly suggest that TFAP2E has a pivotal role in the regulation of DNA damage response in NB cells through the induction of p21

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“…[23]. Oxaliplatin, Fluorouracil, and Leucovorin cause anemia, fever, Vomiting, thrombocytopenia, nausea, diarrhea and neutropenia when used in the treatment of colorectal cancer [24][25][26]. The repurposing of both modified Alpidem and Propoxyphene will be fruitful to cure the effects of colorectal cancer, as both these drugs have fewer signs than the drugs commonly available as better treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

Repurposing of Modified Alpidem and Propoxyphene to Cure AURKA, BCAS1, GNAS and MLH1 Gene Mutations in Colorectal Cancer

Munir¹,

Azam²,

Ali³

et al. 2017

Drug Des

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Background: Colorectal cancer is a varied illness with an expected heritability of 25-30%. Many CRC disorders occur because of solid family history, a high penetrance of the infection, and developing various tumors at an early age. A few novel genes are recognized that shows associations with CRC, such as AURKA, BCAS1, GNAS and MLH1. Material and methods:In this research work FDA rejected Alpidem and Propoxyphene were selected. Drugs were changed on the basis of side effects; modified drugs were docked with AURKA, BCAS1, GNAS and MLH1 proteins and QSAR analysis was performed.Results: Docked and QSAR results demonstrated the better interaction of both modified Alpidem and Propoxyphene along with proteins of CRC causing genes. The toxicity value and side-effects of modified Alpidem and modified Propoxyphene are less than original drugs. Conclusion:The fewer side effects and docking results of both modified Alpidem and Propoxyphene suggest that both the drugs can be used to cure mutations of genes in colorectal cancer as both modified drugs have fewer side-effects and toxicity, as compared to original drugs, both drugs have demonstrated greater interactions with the amino acid residues lying in the pockets of mutated proteins that demonstrates their stability and soundness.

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TFAP2E–DKK4and Chemoresistance in Colorectal Cancer

Cited by 165 publications

References 25 publications

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Formalin-fixed, paraffin-embedded (FFPE) tissue epigenomics using Infinium HumanMethylation450 BeadChip assays

Depletion of TFAP2E attenuates adriamycin-mediated apoptosis in human neuroblastoma cells

Repurposing of Modified Alpidem and Propoxyphene to Cure AURKA, BCAS1, GNAS and MLH1 Gene Mutations in Colorectal Cancer

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