Grasse, Sabrina, Lienhard, Matthias, Frese, Steffen, Kerick, Martin ORCID: 0000-0002-6298-4514, Steinbach, Anne, Grimm, Christina ORCID: 0000-0002-4676-8870, Hussong, Michelle, Rolff, Jana, Becker, Michael, Dreher, Felix, Schirmer, Uwe, Boerno, Stefan, Ramisch, Anna, Leschber, Gunda, Timmermann, Bernd, Grohe, Christian, Lueders, Heike, Vingron, Martin, Fichtner, Iduna, Klein, Sebastian, Odenthal, Margarete, Buettner, Reinhard, Lehrach, Hans, Sueltmann, Holger, Herwig, Ralf and Schweiger, Michal R. (2018). Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Genome Med., 10. LONDON: BMC. ISSN 1756-994X

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Grasse, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lienhard, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frese, SteffenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kerick, MartinUNSPECIFIEDorcid.org/0000-0002-6298-4514UNSPECIFIED
Steinbach, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimm, ChristinaUNSPECIFIEDorcid.org/0000-0002-4676-8870UNSPECIFIED
Hussong, MichelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rolff, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dreher, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schirmer, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boerno, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ramisch, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leschber, GundaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Timmermann, BerndUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grohe, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lueders, HeikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vingron, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fichtner, IdunaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, MargareteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehrach, HansUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sueltmann, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herwig, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schweiger, Michal R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-179625
DOI: 10.1186/s13073-018-0562-1
Journal or Publication Title: Genome Med.
Volume: 10
Date: 2018
Publisher: BMC
Place of Publication: LONDON
ISSN: 1756-994X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PATIENT-DERIVED XENOGRAFTS; CISPLATIN RESISTANCE; CYTOSINE METHYLATION; TUMOR XENOGRAFTS; READ ALIGNMENT; GENE; ACTIVATION; MUTATIONS; INACTIVATION; EXPRESSIONMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17962

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