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Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis.

ABSTRACT: Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p?=?0.019); CD8?+?TILs of BM were significantly lower than lung tumor (10% vs 30%, p?=?0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p?=?0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p?

SUBMITTER: Song Z

PROVIDER: S-EPMC7820277 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis.

Song Zhengbo Z Yang Ling L Zhou Zhipeng Z Li Pansong P Wang Wenxian W Cheng Guoping G Chen Rongrong R Chang Lianpeng L Zhang Yiping Y Guan Yanfang Y Xia Xuefeng X Yi Xin X Zhou Rongrong R Chen Ming M

Cell death & disease 20210121 1

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primar ...[more]

PMID: 33479213

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Project description:Presuming the stage of metastatic lung cancer is divided by its location, an intermediate state of ?5 cumulative metastasis is defined as oligometastases (OM) and a widespread state of >5 cumulative metastasis as polymetastases (PM). According to the phenotypes, the different metastatic cancer patients can be treated with different methods: the OM patients can be treated by a metastasis-directed local therapy method, whereas the PM patients are not recommended to take such a treatment. It is also believed that the patients at the initial OM stage may progress to the PM stage. Currently, the OM- and PM-metastatic cancer patients can be identified by traditional imaging methods. However, the current methods are found to be insufficient for the discrimination. It hence is meaningful and important to develop new diagnostic methods for a better prediction to the patients following by selecting a correct metastasis-directed treatment.MicroRNAs (miRNAs) can be used as the genetic probes for the new diagnostic methods. In this study, a bioinformatics strategy was employed to screen the microRNAs as potential diagnostic probes for distinguishing the OM and PM lung metastases patients. The expression profiles of microarray data of GSE38698 were downloaded from Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) including the information from 63 patients: 24 PM and 39 OM patients. The microRNA expression patterns of tumor samples were identified for the OM and PM patients who were treated with the high-dose radiotherapy. Followed by analyzing the functional enrichment pathways, an early diagnosis model of OM and PM groups was identified with different expression genes (DEGs). The ratios of PM/OM were calculated by setting a high significance in the expressions of 377 mature miRNAs in the profile [log2?(PM/OM) >1 and P?<?.05]. Through a high combination power [area under the curve (AUC) ? 0.875] with the superior sensitivity and specificity, a panel of 10 miRNAs including 7 upregulation and 3 downregulation expressions were identified as potential probes for discriminating the PM and OM patients from the receiving operation characteristic (ROC). Considering the possible involvements of cancer progress, the interconnected axon guidance, cancer metastasis pathways, proteoglycans, and Mitogen-activated protein kinases signaling pathway and endocytosis were suggested for the subsequent miRNA target analysis. The results may reveal a biological significance that a profile of miRNAs can be used as the potential probes to identify the patients at the OM or PM stages and figure out the metastasis-directed treatment methods for the patients at the different metastasis stages.

Dataset Information

Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis.

Publications

Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis.

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