English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  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.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/21.11116/0000-0002-5FA6-9 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-5FA7-8
Genre: Journal Article

Files

show Files
hide Files
:
Grasse.pdf (Publisher version), 3MB
Name:
Grasse.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© The Author(s). 2018

Locators

show

Creators

show
hide
 Creators:
Grasse, Sabrina, Author
Lienhard, Matthias1, Author              
Frese, Steffen, Author
Kerick, Martin , Author
Steinbach, Anne, Author
Grimm, Christina, Author
Hussong, Michelle , Author
Rolff, Jana, Author
Becker, Michael, Author
Dreher, Felix, Author
Schirmer, Uwe, Author
Boerno, Stefan T.2, Author              
Ramisch, Anna3, Author              
Leschber, Gunda , Author
Timmermann, Bernd2, Author              
Grohé, Christian , Author
Lüders, Heike, Author
Vingron, Martin4, Author              
Fichtner, Iduna, Author
Klein, Sebastian, Author
Odenthal, Margarete, AuthorBüttner, Reinhard, AuthorLehrach, Hans5, Author              Sültmann, Holger, AuthorHerwig, Ralf1, Author              Schweiger, Ruth M., Author more..
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              

Content

show
hide
Free keywords: Carboplatin resistance; DNA methylation; Epigenomics; NSCLC; Non-small cell lung cancer; Patient-derived xenografts; Predictive biomarker; Therapy response
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2018-06-212018-07-20
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1186/s13073-018-0562-1
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Genome Medicine
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 10 (1) Sequence Number: 10:55 Start / End Page: - Identifier: -