Development and validation of a five-gene model to predict postoperative brain metastasis in operable lung adenocarcinoma
Fangqiu Fu
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYang Zhang
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorZhendong Gao
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYue Zhao
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorZhexu Wen
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorHan Han
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYuan Li
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
Search for more papers by this authorCorresponding Author
Haiquan Chen
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Correspondence to: Haiquan Chen, E-mail: [email protected]Search for more papers by this authorFangqiu Fu
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYang Zhang
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorZhendong Gao
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYue Zhao
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorZhexu Wen
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorHan Han
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Search for more papers by this authorYuan Li
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China
Search for more papers by this authorCorresponding Author
Haiquan Chen
Department of Thoracic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
Institute of Thoracic Oncology, Fudan University, Shanghai, China
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Correspondence to: Haiquan Chen, E-mail: [email protected]Search for more papers by this authorAbstract
One of the most common sites of extra-thoracic distant metastasis of nonsmall-cell lung cancer is the brain. Our study was performed to discover genes associated with postoperative brain metastasis in operable lung adenocarcinoma (LUAD). RNA seq was performed in specimens of primary LUAD from seven patients with brain metastases and 45 patients without recurrence. Immunohistochemical (IHC) assays of the differentially expressed genes were conducted in 272 surgical-resected LUAD specimens. LASSO Cox regression was used to filter genes related to brain metastasis and construct brain metastasis score (BMS). GSE31210 and GSE50081 were used as validation datasets of the model. Gene Set Enrichment Analysis was performed in patients stratified by risk of brain metastasis in the TCGA database. Through the initial screening, eight genes (CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK) were selected for IHC analyses. The BMS based on protein expression levels of five genes (TYMS, CDK1, HJURP, CEP55 and KIF11) was highly predictive of brain metastasis in our cohort (12-month AUC: 0.791, 36-month AUC: 0.766, 60-month AUC: 0.812). The validation of BMS on overall survival of GSE31210 and GSE50081 also showed excellent predictive value (GSE31210, 12-month AUC: 0.682, 36-month AUC: 0.713, 60-month AUC: 0.762; GSE50081, 12-month AUC: 0.706, 36-month AUC: 0.700, 60-month AUC: 0.724). Further analyses showed high BMS was associated with pathways of cell cycle and DNA repair. A five-gene predictive model exhibits potential clinical utility for the prediction of postoperative brain metastasis and the individual management of patients with LUAD after radical resection.
Abstract
What's new?
Non-small-cell lung cancer often metastasizes to the brain. Are there specific genes that increase this tendency? In this study, the authors used gene-set enrichment analysis, RNA sequencing, and immunohistochemical assays to develop a model to predict brain metastasis. The resulting “brain metastasis score” (BMS) identified five genes that are highly predictive. Further analyses indicated that a high BMS is associated with cell-cycle and DNA-repair pathways. Determining which patients have a high-risk BMS may guide special prophylactic management.
Conflict of interest
The authors have no conflict of interest to disclose.
Supporting Information
| Filename | Description |
|---|---|
| ijc32981-sup-0001-supinfo.pdfPDF document, 7.8 MB | Figure S1 Typical images of low and high expression of CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK (20×, 50× and 200×) in 272 surgically resected specimens. Figure S2. The immunoreactivity score of eight enrolled genes in 15 patients who also received RNA-seq. Figure S3. The validation of BMS on overall survival in GSE31210 and GSE50081. (a, c) ROC curve analyses of the prognostic value of BMS in GSE31210 (a) and GSE50081 (c) as the validation datasets at 12, 36 and 60 months. (b, d) Comparison of overall survival in patients of GSE31210 (b) and GSE50081 (d) with low BMS versus those with high BMS. Table S1. The correlation of recurrence information and corresponding RNA barcodes in EGAS00001004006. Table S2. Clinicopathologic characteristics of 52 lung adenocarcinoma patients receiving RNA sequencing. Table S3. The 326 differentially expressed genes in primary lung cancer with brain metastasis. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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