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  Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance

Grasse, S., Lienhard, M., Frese, S., Kerick, M., Steinbach, A., Grimm, C., et al. (2018). Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Medicine, 10(1): 10:55. doi:10.1186/s13073-018-0562-1.

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© The Author(s). 2018

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 Urheber:
Grasse, Sabrina, Autor
Lienhard, Matthias1, Autor           
Frese, Steffen, Autor
Kerick, Martin , Autor
Steinbach, Anne, Autor
Grimm, Christina, Autor
Hussong, Michelle , Autor
Rolff, Jana, Autor
Becker, Michael, Autor
Dreher, Felix, Autor
Schirmer, Uwe, Autor
Boerno, Stefan T.2, Autor           
Ramisch, Anna3, Autor           
Leschber, Gunda , Autor
Timmermann, Bernd2, Autor           
Grohé, Christian , Autor
Lüders, Heike, Autor
Vingron, Martin4, Autor           
Fichtner, Iduna, Autor
Klein, Sebastian, Autor
Odenthal, Margarete, AutorBüttner, Reinhard, AutorLehrach, Hans5, Autor           Sültmann, Holger, AutorHerwig, Ralf1, Autor           Schweiger, Ruth M., Autor mehr..
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
4Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
5Emeritus Group of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385697              

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Schlagwörter: Carboplatin resistance; DNA methylation; Epigenomics; NSCLC; Non-small cell lung cancer; Patient-derived xenografts; Predictive biomarker; Therapy response
 Zusammenfassung: BACKGROUND:

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed.
METHODS:

Here, we employed patient-derived xenografts (PDXs) to detect predictive methylation biomarkers for platin-based therapies. We used MeDIP-Seq to generate genome-wide DNA methylation profiles of 22 PDXs, their parental primary NSCLC, and their corresponding normal tissues and complemented the data with gene expression analyses of the same tissues. Candidate biomarkers were validated with quantitative methylation-specific PCRs (qMSP) in an independent cohort.
RESULTS:

Comprehensive analyses revealed that differential methylation patterns are highly similar, enriched in PDXs and lung tumor-specific when comparing differences in methylation between PDXs versus primary NSCLC. We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy. This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin. Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p < 0.01). Similarly, we find a shorter survival time for patients with LRP12 hypermethylation in the TCGA data set for NSCLC (lung adenocarcinoma).
CONCLUSIONS:

Using an epigenome-wide sequencing approach, we find differential methylation patterns from primary lung cancer and PDX-derived cancers to be very similar, albeit with a lower degree of differential methylation in primary tumors. We identify LRP12 DNA methylation as a powerful predictive marker for carboplatin resistance. These findings outline a platform for the identification of epigenetic therapy resistance biomarkers based on PDX NSCLC models.

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Sprache(n): eng - English
 Datum: 2018-06-212018-07-20
 Publikationsstatus: Online veröffentlicht
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
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 Identifikatoren: DOI: 10.1186/s13073-018-0562-1
 Art des Abschluß: -

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Titel: Genome Medicine
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 10 (1) Artikelnummer: 10:55 Start- / Endseite: - Identifikator: -