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

Abstract

BackgroundNon-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.MethodsHere, 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.ResultsComprehensive 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).ConclusionsUsing 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.Electronic supplementary materialThe online version of this article (10.1186/s13073-018-0562-1) contains supplementary material, which is available to authorized users.

The fidelity of cancer cells in PDX models: Characteristics, mechanism and clinical significance

“…The aforementioned genomic, transcriptional and proteomic study results indicate that the molecular characteristics of cancer cells in PDX models may change during engraftment. A recent NSCLC study suggested that the epigenome may evolve: the genome‐wide DNA methylation profile of xenograft tumors was poorly correlated with that of parental tumors . However, none of these studies have accounted for the constantly changing phenotype .…”

Novel Breast Cancer Brain Metastasis Patient-Derived Orthotopic Xenograft Model for Preclinical Studies

“…The patient-derived xenograft (PDX) model of cancer is created by transplanting tumor tissue in immunodeficient mice at the same (orthotopic) or different (ectopic) anatomic site. PDXs retain genetic, transcriptional and phenotypic features of the original tumor even after long-term continuous passage in vivo [16][17][18][19][20][21], and they have been used successfully to develop new therapies for cancers [22,23]. Subcutaneous breast cancer PDXs are often used for pre-clinical drug screening because both tumor transplantation and tumor tracking are easy.…”

Epigenetic activation of FOXF1 confers cancer stem cell properties to cisplatin‑resistant non‑small cell lung cancer

“…The mechanisms responsible for resistance to chemotherapy are complex, and are related to several factors, such as drug uptake, cell cycle, DNA repair and others; the molecular mechanisms responsible for chemotherapeutic resistance have not yet been fully elucidated (18,19). Recently, it was found that the abnormal DNA methylation of the genome plays an important role in the chemotherapy resistance of cancers, including NSCLC (20,21). It was found that platinum-based chemotherapy can influence DNA methylation modification in cancer (22).…”