Dataset Information

Predictive modelling of brain metastasis development from cancer and non-invasive biomarker-based risk assessment leveraging DNA methylation signatures

ABSTRACT: Brain metastases (BM) are the most common and among the most deadly brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, limiting early intervention. Here, we obtained 364 tumor/plasma samples from a large cohort of lung adenocarcinoma (LUAD) and BM patients (N=309), the most common BM source. LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, which was integrated with clinical factors to provide comprehensive patient-specific BM risk probabilities in a nomogram. Additionally, immune and cell interaction gene sets were differentially methylated at promoters in BM versus paired primary LUAD and had aligning dysregulation in the proteome. Immune cells were differentially abundant in BM versus LUAD. Finally, liquid biomarkers identified from methylated cell-free DNA sequenced in plasma were used to generate and validate accurate classifiers for early BM detection. Overall, LUAD methylomes can be leveraged to predict and non-invasively identify BM with high precision, moving towards improved patient outcomes with personalized treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos, Bruker Daltonics instrument model

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Lung

DISEASE(S): Lung Cancer

SUBMITTER: Michael Moran

LAB HEAD: Michael F. Moran

PROVIDER: PXD048525 | Pride | 2025-03-21

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	Brain-Metastasis-Library-Generation-Peak-List.7z	Other
	Brain-Metastasis-Library-Generation-Peptide-Identification-Files.7z	Other
	Brain-Metastasis-Library-Raw-Data.7z	Other
	Brain-Metastasis-Library.7z	Other
	Brain-Metastasis-Samples-DIA-NN-Results.7z	Other

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Publications

Prediction of brain metastasis development with DNA methylation signatures.

Zuccato Jeffrey A JA Mamatjan Yasin Y Nassiri Farshad F Ajisebutu Andrew A Liu Jeffrey C JC Muazzam Ammara A Singh Olivia O Zhang Wen W Voisin Mathew M Mirhadi Shideh S Suppiah Suganth S Wybenga-Groot Leanne L Tajik Alireza A Simpson Craig C Saarela Olli O Tsao Ming S MS Kislinger Thomas T Aldape Kenneth D KD Moran Michael F MF Patil Vikas V Zadeh Gelareh G

Nature medicine 20241008 1

Brain metastases (BMs) are the most common and among the deadliest brain tumors. Currently, there are no reliable predictors of BM development from primary cancer, which limits early intervention. Lung adenocarcinoma (LUAD) is the most common BM source and here we obtained 402 tumor and plasma samples from a large cohort of patients with LUAD with or without BM (n = 346). LUAD DNA methylation signatures were evaluated to build and validate an accurate model predicting BM development from LUAD, w ...[more]

PMID: 39379704

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Project description:Metastases in the brain are the most severe and devastating complication of cancer. The incidence of brain metastasis is increasing. Therefore, the need of finding specific druggable targets for brain metastasis is demanding. The aim of this study was to compare the brain (immune) response to brain metastases of the most common tumor lineages, viz., lung adenocarcinoma and breast cancer. Targeted gene expression profiles of 11 brain metastasis of lung adenocarcinoma (BM-LUAD) were compared to 11 brain metastasis of breast cancer (BCBM) using NanoString nCounter PanCancer IO 360™ Panel. The most promising results were validated spatially using the novel GeoMx™ Digital Spatial Profiler (DSP) Technology. Additionally, Immune cell profiles and expression of drug targets were validated by multiplex immunohistochemistry. We found more active immune response in BM-LUAD as compared to BCBM. In the BM-LUAD, 138 genes were upregulated as compared to BCBM (adj. p ≤ 0.05). Conversely, in BCBM 28 genes were upregulated (adj. p ≤ 0.05). Additionally, genes related to CD45+ cells, T cells and cytotoxic T cells showed to be expressed higher in BM-LUAD compared to BCBM (adj. p = 0.01, adj. p = 0.023, adj. p = 0.023, respectively). The spatial quantification of the immune cells using the GeoMx DSP technique revealed the significantly higher quantification of CD14 and CD163 in tumor regions of BM-LUAD as compared to BCBM. Importantly, the immune checkpoint VISTA and IDO1 were identified as highly expressed in the BM-LUAD. Multiplex immunohistochemistry confirmed the finding and showed that VISTA is expressed mainly in BM-LUAD tumor cells, CD3+ cells, and to less levels in some microglial cells in BM-LUAD. This is the first report on differences in the brain immune response between metastatic tumor of different lineages. We found a far more extensive infiltration of immune cells in BM-LUAD as compared to BCBM. In addition, we found higher expression of VISTA and IDO1 in BM-LUAD. Taken together, targeted immune therapy should be considered to treat patients with BM-LUAD.

Project description:Introduction: The incidence of brain metastases in cancer patients is increasing, with lung and breast cancer being the most common sources. Despite advancements in targeted therapies, the prognosis remains poor, highlighting the importance to investigate the underlying mechanisms in brain metastases. The aim of this study was to investigate the differences in the molecular mechanisms involved in brain metastasis of breast and lung cancers. In addition, we aimed to identify cancer lineage-specific druggable targets in the brain metastasis. Methods: To that aim, a cohort of 44 FFPE tissue samples, including 22 breast cancer and 22 lung adenocarcinoma (LUAD) and their matched-paired brain metastases were collected. Targeted gene expression profiles of primary tumors were compared to their matched-paired brain metastases samples using nCounter PanCancer IO 360™ Panel of NanoString technologies. Pathway analysis was performed using gene set analysis (GSA) and gene set enrichment analysis (GSEA). The validation was performed by using Immunohistochemistry (IHC) to confirm the expression of immune checkpoint inhibitors. Results: Our results revealed the significant upregulation of cancer-related genes in primary tumors compared to their matched-paired brain metastases (adj. p ≤ 0.05). We found that upregulated differentially expressed genes in breast cancer brain metastasis (BM-BC) and brain metastasis from lung adenocarcinoma (BM-LUAD) were associated with the metabolic stress pathway, particularly related to the glycolysis. Additionally, we found that the upregulated genes in BM-BC and BM-LUAD played roles in immune response regulation, tumor growth, and proliferation. Importantly, we identified high expression of the immune checkpoint VTCN1 in BM-BC, and VISTA, IDO1, NT5E, and HDAC3 in BM-LUAD. Validation using immunohistochemistry further supported these findings. Conclusion: In conclusion, the findings highlight the significance of using matched-paired samples to identify cancer lineage-specific therapies that may improve brain metastasis patients outcomes.