Abstract
Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities. To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). Using supervised machine learning and integration of DNA methylomes from normal, primary, and metastatic tumor specimens (n = 1860), we unravel epigenetic signatures specific to each type of metastatic brain tumor and constructed a three-step DNA methylation-based classifier (BrainMETH) that categorizes brain metastases according to the tissue of origin and therapeutically relevant subtypes. BrainMETH predictions are supported by routine histopathologic evaluation. We further characterize and validate the most predictive genomic regions in a large cohort of brain tumors (n = 165) using quantitative-methylation-specific PCR. Our study highlights the importance of brain tumor-defining epigenetic alterations, which can be utilized to further develop DNA methylation profiling as a critical tool in the histomolecular stratification of patients with brain metastases.
Highlights
Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities
To decrease potential biases associated with the gender of Brain metastases (BM) patients, we excluded 105,422 probes recognizing regions located in sex chromosomes or with proven cross-reactivity with sex chromosomes21,22. 2983 probes with a detection P-value greater than 0.01 (‘NA’) in any specimen were excluded from this study
Using the HumanMethylation 450K (HM450K) data, we found that by surveying at least two of these genomic regions hypermethylated in BM we could distinguish primary from metastatic brain tumors with significant accuracy (Area under the curve (AUC) > 0.90; Supplementary Fig. 2b)
Summary
Optimal treatment of brain metastases is often hindered by limitations in diagnostic capabilities To meet this challenge, here we profile DNA methylomes of the three most frequent types of brain metastases: melanoma, breast, and lung cancers (n = 96). While systemic chemotherapy has limited efficacy, targeted therapies have recently shown promise for oncologic management[6] These tailored therapies have significantly affected treatment decisionmaking for patients with breast cancer BM (BCBM). A major limitation in achieving an accurate pathological diagnosis is the often poor differentiation and/or limited availability of metastatic brain tumor tissues to evaluate the complete panel of IHC markers[9]. DNA methylation (DNAm) profiling was recently shown to be a powerful analytical tool to identify the origin of cancers from unknown primary sites and to better stratify patients with primary central nervous system (CNS) tumors[12,13]. We have shown that DNAm profiling can be efficiently performed using small samples of BM tissues[14,15,16,17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
