Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis

• Published in: Nature communications Vol. 14; no. 1; pp. 4980 - 11
• Main Authors: Skakodub, Anna, Walch, Henry, Tringale, Kathryn R., Eichholz, Jordan, Imber, Brandon S., Vasudevan, Harish N., Li, Bob T., Moss, Nelson S., Hei Yu, Kenny Kwok, Mueller, Boris A., Powell, Simon, Razavi, Pedram, Yu, Helena A., Reis-Filho, Jorge S., Gomez, Daniel, Schultz, Nikolaus, Pike, Luke R. G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.08.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/23; 631/67/1612/1350; 631/67/322; 692/4028/67/1922; 692/4028/67/69; Brain; Brain cancer; Brain Neoplasms - genetics; Carcinoma, Non-Small-Cell Lung - genetics; Cell cycle; Epidermal growth factor receptors; ErbB Receptors - genetics; Genomic analysis; Genomics; Humanities and Social Sciences; Humans; Lung cancer; Lung Neoplasms - genetics; Meninges; Metastases; Metastasis; multidisciplinary; Myc protein; Non-small cell lung carcinoma; Regional development; Science; Science (multidisciplinary); Small cell lung carcinoma; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40793-x

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression. The genomic landscape of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) remains to be explored. Here, the authors analyse a cohort of 233 patients with BM including 47 primary tumour, 42 extracranial metastatic matched samples and reveal distinct mutational patterns.