Genomic Profiling Identifies Putative Pathogenic Alterations in NSCLC Brain Metastases.

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.