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Genomic profiling identifies putative pathogenic alterations in non-small cell lung cancer brain metastases

Open AccessPublished:November 09, 2022DOI:https://doi.org/10.1016/j.jtocrr.2022.100435
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      Abstract

      Introduction

      Brain metastases (BM) severely impact the prognosis and quality of life of patients with non-small cell lung cancer (NSCLC). Recently, molecularly targeted agents have shown promising activity against BM in NSCLC patients whose primary tumors carry ‘druggable’ mutations. However, it remains critical to identify specific pathogenic alterations that drive NSCLC-BM and that can provide novel and more effective therapeutic targets.

      Methods

      To identify potentially targetable pathogenic alterations in NSCLC-BM, we profiled somatic copy number alterations (SCNAs) in 51 matched pairs of primary NSCLC and BM samples from 33 patients with lung adenocarcinoma (LUAD) and 18 patients with lung squamous cell carcinoma (LUSC). Additionally, we performed multi-region copy number profiling on 15 BM samples and whole-exome sequencing (WES) on 40 out of 51 NSCLC-BM pairs.

      Results

      BM consistently had a higher burden of SCNAs compared to the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, suggesting that BM do not undergo extensive evolution once formed. By comparing focal SCNAs in matched NSCLC-BM pairs, we identified putative BM driving alterations affecting multiple cancer genes, including several potentially targetable alterations in genes such as CDK12, DDR2, ERBB2, and NTRK1, which we validated in an independent cohort of 84 BM samples. Finally, we identified putative pathogenic alterations in multiple cancer genes, including genes involved in epigenome editing and 3D genome organization, such as EP300, CTCF, and STAG2, which we validated by targeted sequencing of an independent cohort of 115 BM samples.

      Conclusions

      Our study represents the most comprehensive genomic characterization of NSCLC-BM available to date, paving the way to functional studies aimed at assessing the potential of the identified pathogenic alterations as clinical biomarkers and targets.

      Keywords