Abstract
Brain metastasis (BM) is the primary contributor to mortality in non‐small cell lung cancer (NSCLC) patients. Although the findings of NSCLC genetic sequencing studies suggest the potential for personalizing therapeutic approaches, the genetic profiles and underlying mechanisms of BM progression remain poorly understood. Here, we investigated the genetic profiles of brain metastases from NSCLC in six patients with primary tumors and corresponding BM samples via whole exome sequencing and targeted panel sequencing. We have demonstrated considerable genetic heterogeneity between primary lung cancer and corresponding brain metastases specimens. High‐frequency mutations were found in NOTCH2,NOTCH2NL,FANCD2,EGFR, and TP53. Additionally, EGFR and TP53 consistently exhibited high frequencies of mutation between primary tumors and corresponding brain metastases. The implication is that most of the genetic alterations may be acquired or lost during malignant progression, and the stable EGFR and TP53 mutational status between paired primary tumors and metastatic sites confirms that most mutations detected on analysis of the primary tumor or metastases are sufficient for clinical decision‐making, and suggest there is no need to re‐biopsy recurrent tumors or metastases for most NSCLC patients.
Highlights
Brain metastasis (BM) is the primary contributor to mortality in non-small cell lung cancer (NSCLC) patients
The implication is that most of the genetic alterations may be acquired or lost during malignant progression, and the stable EGFR and TP53 mutational status between paired primary tumors and metastatic sites confirms that most mutations detected on analysis of the primary tumor or metastases are sufficient for clinical decision-making, and suggest there is no need to re-biopsy recurrent tumors or metastases for most NSCLC patients
Even though we observed high genetic heterogeneity in paired primary tumors and brain parenchyma metastases, we found that mutations in EGFR and TP53 were highly concordant between paired primary tumors and brain metastases (100% concordance), the same as the concordance reported by Matsumoto et al [18]
Summary
Brain metastasis (BM) is the primary contributor to mortality in non-small cell lung cancer (NSCLC) patients. We investigated the genetic profiles of brain metastases from NSCLC in six patients with primary tumors and corresponding BM samples via whole exome sequencing and targeted panel sequencing. We have demonstrated considerable genetic heterogeneity between primary lung cancer and corresponding brain metastases specimens. EGFR and TP53 consistently exhibited high frequencies of mutation between primary tumors and corresponding brain metastases. The heterogeneity of molecular profiles between primary tumors and brain metastases or heterogeneity that develops during the malignant process may limit the efficacy of individual treatments. Abbreviations BM, brain metastasis; BP, biological process; CC, cellular components; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MF, molecular functions; NSCLC, non-small cell lung cancer; SNV, somatic nucleotide variant; WES, whole exome sequencing.
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