Brain metastasis (BM) is a frequent event in patients with lung adenocarcinoma (LUAD) and BM can respond discordantly to systemic therapy compared to extracranial disease resulting in often dismal prognosis. Therefore, there has been an increasing interest to better understand the biology of BM. However, most publications focused on the genomic differences between the primary tumor and its metastases and data on changes on the transcriptional and especially epigenetic level is scarce. In this study, we investigated the methylation changes between primary LUAD and paired BM.
We conducted a retrospective single center study including all treatment naïve patients with sufficient tissue from paired synchronous LUAD and BM resected between 2000–2019. DNA was extracted from archived formalin-fixed paraffin-embedded sections after macrodissection of the region of interest. Methylation profiling was done with the Infinium MethylationEPIC v1.0®.
Methylation profiling was possible for 24 patients. Five patients were excluded due to low DNA quality. The principal component analysis depicted a high similarity between primary LUAD and paired BM, whereas normal control tissue clustered separately and by organ (lung respectively brain). Unsupervised hierarchical clustering confirmed these results with the most discriminatory feature being the patient and not the origin of tissue. Most sites were hypomethylated in the BM as compared to the LUAD. These hypomethylated sites were often not associated to islands and located in the gene body. However, hypermethylated sites were associated to islands and more often located in potential promotor regions. The MAPK signaling pathway was the most differentially methylated pathway.
Only subtle differences are present when comparing LUAD and paired BM on the methylome level. These differences are primarily characterized by hypomethylation in the gene bodies and hypermethylation in promotor regions. Our results confirm the importance of the MAPK pathway (including EGFR and KRAS) at the epigenetic level which has also been described on the genomic level.
Legal entity responsible for the study
Cancer Research Switzerland.
S. Berezowska: Financial Interests, Institutional, Advisory Board: Daiichi-Sankyo, Eli Lilly, Merck; Financial Interests, Institutional, Other, active participation in webinar: BMS. All other authors have declared no conflicts of interest.