Abstract
BackgroundBrain metastases (BM) are the most common intracranial tumors. 2–14% of BM patients present with unknown primary site despite intensive evaluations. This study aims to evaluate the performance of a 90-gene expression signature in determining the primary sites for BM samples.MethodsThe sequence-based gene expression profiles of 708 primary brain tumors (PBT) collected from The Cancer Genome Atlas (TCGA) database were analyzed by the 90-gene expression signature, with a similarity score for each of 21 common tumor types. We then used Optimal Binning algorithm to generate a threshold for separating PBT from BM. Eighteen PBT samples were analyzed to substantiate the reliability of the threshold. In addition, the performance of the 90-gene expression signature for molecular classification of metastatic brain tumors was validated in a cohort of 48 BM samples with the known origin. For each BM sample, the tumor type with the highest similarity score was considered tissue of origin. When a sample was diagnosed as PBT, but the similarity score below the threshold, the second prediction was considered as the primary site.ResultsA threshold of the similarity score, 70, was identified to discriminate PBT from BM (PBT: > 70, BM: ≤ 70) with an accuracy of 99% (703/708, 95% CI 98–100%). The 90-gene expression signature was further validated with 18 PBT and 44 BM samples. The results of 18 PBT samples matched reference diagnosis with a concordance rate of 100%, and all similarity scores were above the threshold. Of 44 BM samples, the 90-gene expression signature accurately predicted primary sites in 89% (39/44, 95% CI 75–96%) of the cases.ConclusionsOur findings demonstrated the potential that the 90-gene expression signature could serve as a powerful tool for accurately identifying the primary sites of metastatic brain tumors.
Highlights
Brain metastases (BM) are the most common intracranial tumors. 2–14% of BM patients present with unknown primary site despite intensive evaluations
Brain metastases (BM) are the most common neoplasms encountered in the central nervous system (CNS) and continue to be a major cause of mortality
Recent studies found that Vemurafenib, a selective inhibitor of BRAFV600, has shown significant response rate in BRAFV600 melanoma [11, 12], but not in metastatic BRAFV600 colorectal cancers [13], indicating the fundamentality of tumor tissue origin in molecular targeted therapy
Summary
Brain metastases (BM) are the most common intracranial tumors. 2–14% of BM patients present with unknown primary site despite intensive evaluations. Recent studies found that Vemurafenib, a selective inhibitor of BRAFV600, has shown significant response rate in BRAFV600 melanoma [11, 12], but not in metastatic BRAFV600 colorectal cancers [13], indicating the fundamentality of tumor tissue origin in molecular targeted therapy. Clinical symptoms, tumor markers, and imaging analysis help characterize the origin of metastatic neoplasms. These conventional approaches would get into the puzzle when the presumed primary tumor metastasizes before becoming large enough to be identified [14]. Histopathology remains crucial for determining the anatomical origin and histological type of BMs. non-specific or inconclusive tissue morphology and immunohistochemical findings can confound, when metastatic tumors are poorly differentiated or undifferentiated. Previous studies reported histopathological accuracies for diagnosing the primary site of BMs as low as 72.5% [16]
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