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.
Background
Although AJCC/TNM staging remains the gold standard for prognostic assessment of colon cancer, stage-specific outcomes vary. We therefore prospectively evaluated the prognostic role of immunoprofiling.
Methods
Our cohort included 35 patients from an ongoing prospective trial of ultrastaging for colon cancer. Specimens were analyzed for T cell markers (CD3, CD4, CD8, and FoxP3). The number of tumor-infiltrating lymphocytes was analyzed at the tumor’s margin and center and correlated with AJCC/TNM stage, clinicopathologic variables, and disease-free survival.
Results
There was a significant inverse association between number of CD3+ cells in the tumor center and tumor stage (P=0.05). The tumor center/margin ratio of CD3+ cells also showed an inverse but non-significant relationship with nodal involvement (P=0.07). Body mass index was inversely associated with numbers of CD3+(P=0.04) and CD8+(P=0.02) cells. Longer disease-free survival was correlated with higher CD8+ counts (P=0.07), lower CD4+/CD8+ ratios (P=0.008), and higher CD8+/FoxP3+ ratios (P=0.02).
Conclusions
This is the first prospective validation of immunoprofiling in patients whose colon cancer is staged with strict surgical and pathology quality measures. The apparent correlation between immunophenotypic response and clinical outcome warrants evaluation in a larger prospective trial.
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