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Genomic Profiling Identifies Putative Pathogenic Alterations in NSCLC Brain Metastases
Marcin Nicoś1,2,3, Luuk Harbers1,2, Enrico Patrucco4
1Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
Introduction:
Brain metastases (BM) severely affect the prognosis and quality of life of patients with NSCLC. Recently, molecularly targeted agents were found to have promising activity against BM in patients with NSCLC whose primary tumors carry "druggable" mutations. Nevertheless, 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 and 18 patients with lung squamous cell carcinoma. In addition, we performed multiregion copy number profiling on 15 BM samples and whole-exome sequencing on 40 of 51 NSCLC-BM pairs.
Results:
BM consistently had a higher burden of SCNAs compared with the matched primary tumors, and SCNAs were typically homogeneously distributed within BM, suggesting 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.
Insights
This study identified key genetic alterations driving non-small cell lung cancer brain metastases (NSCLC-BM). These findings reveal potential new therapeutic targets for improving patient outcomes.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Brain metastases (BM) significantly worsen prognosis and quality of life for non-small cell lung cancer (NSCLC) patients.
- Targeted therapies show promise for NSCLC-BM with "druggable" mutations, but identifying specific drivers is crucial for novel treatments.
Purpose of the Study:
- To identify potentially targetable pathogenic alterations driving NSCLC-BM.
- To characterize the genomic landscape of NSCLC-BM compared to primary tumors.
Main Methods:
- Somatic copy number alterations (SCNAs) profiling of 51 matched primary NSCLC and BM samples.
- Multiregion copy number profiling of 15 BM samples and whole-exome sequencing of 40 NSCLC-BM pairs.
- Validation of identified alterations in independent cohorts of BM samples.
Main Results:
- BM exhibited a higher burden of SCNAs than matched primary tumors, with homogeneous distribution within BM.
- Identified putative BM-driving alterations in genes like CDK12, DDR2, ERBB2, and NTRK1.
- Discovered pathogenic alterations in epigenome editing and 3D genome organization genes (EP300, CTCF, STAG2).
Conclusions:
- This study provides the most comprehensive genomic characterization of NSCLC-BM to date.
- Identified pathogenic alterations represent potential clinical biomarkers and therapeutic targets for NSCLC-BM.
