Brain metastases (BM) are the most common intracranial tumors affecting about 8-10% of all cancer patients. Morphology and immunohistochemical staining are two common approaches used to identify the primary sites of BM samples, but morphology fails to identify poorly differentiated tumors and IHC markers usually lack specificity. About 2% to 14% of BM patients still present with unknown primary sites. A 90-gene assay, proposed in our previous study, is an RNA-based gene expression test to identify the tissue of origin in poorly differentiated and undifferentiated tumors. This study aims to evaluate the performance of the 90-gene assay in determining the primary sites for BM samples.
The sequence-based gene expression profiles of 708 primary brain tumors (PBT) collected from The Cancer Genome Atlas database were performed by a 90-gene expression signature, with a similarity score for each of 21 tumor types. We used Optimal Binning algorithm to generate a threshold for separating PBT from BM. Eighteen PBT samples from Fudan University Shanghai Cancer Center were analyzed to substantiate reliability of the threshold. In addition, the performance of the 90-gene assay for identifying the tissue of origin was validated in a cohort of 48 BM samples with known origin from The First Affiliated Hospital, Zhejiang University. 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 primary site.
A threshold of the similarity score, 70, was identified to discriminate PBT from BM (PBT: ≥ 70, BM: < 70) with an accuracy of 99% (703/708). Eighteen PBT and 44 BM were performed by the 90-gene assay. The results of 18 PBT samples matched reference diagnosis with a concordance rate of 100% and all similarity scores were above 70. Of 44 BM samples, the 90-gene assay accurately predicted primary sites in 89% (39/44, 95%CI: 0.75-0.96) of the cases.
The 90-gene assay showed promising discriminatory ability to separate PBT from BM and identify the primary site of BM. Our findings demonstrated the potential that 90-gene assay can serve as a powerful tool for accurately identifying the tissue of origin for BM samples.
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Y. Sun, C. Chen, L. Chen, J. Zhu: Employment: Canhelp Genomics Co. Ltd. Q. Xu: Employment, stock ownership: Canhelp Genomics Co. Ltd. All other authors have declared no conflicts of interest.