Christian Grohé, Margarete Odenthal, Sebastian Klein, Ralf Herwig, Heike Lüders, Anne Steinbach, Uwe Schirmer, Reinhard Büttner, Bernd Timmermann, Christina Grimm, Stefan Boerno, Steffen Frese, Jana Rolff, Gunda Leschber, Michael Becker, Martin Kerick, Michelle Hussong, Martin Vingron, Matthias Lienhard, Hans Lehrach, Anna Ramisch, Michal R. Schweiger, Sabrina Grasse, Holger Sültmann, Felix Dreher, Iduna Fichtner, Volkswagen Foundation, Federal Ministry of Education and Research (Germany), University of Cologne, Staatskanzlei des Landes Nordrhein-Westfalen, and German Research Foundation
[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, [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., This work was supported by the Volkswagenstiftung (Lichtenberg program to MRS), the German Federal Ministry of Education and Research (0316190A (EPITREAT), the Center for Molecular Medicine Cologne (CMMC), the state of North Rhine-Westphalia (EFRE-0800397), and the German Research Foundation (DFG KFO286).