Whole-genome profiling to identify chromosomal instability as a distinct feature of lung cancer brain metastases.

Abstract

e20554 Background: Brain metastases in lung cancer are associated with substantial clinical heterogeneity and poor outcomes, yet underlying molecular mechanisms remain incompletely understood. Previous studies on brain metastases have been limited by the scarcity of in-depth whole-genome sequencing (WGS) data , resulting in insufficient characterization of chromosomal instability (CIN) and fine-scale genomic architecture. This knowledge gap has significantly hindered our understanding of brain metastasis initiation, evolutionary trajectories, and inter-lesion heterogeneity. Methods: Patients diagnosed with lung cancer and brain metastases were retrospectively identified, and frozen samples from these brain metastases, with or withou primary tumors, were available for analysis. High depth whole-genome sequencing (WGS) at 200× coverage was performed to characterize somatic driver alterations and chromosomal instability (CIN). CIN was assessed using genome-wide copy number alteration burden, whole-genome doubling (WGD), and structural variation profiles. Genomic differences between brain metastases and non-brain lesions were evaluated through comparative analyses, with exploratory links to clinical features examined. Results: Whole-genome sequencing of 83 lung cancer brain metastases revealed a high prevalence of chromosomal instability. Among these tumors, 26 were near-diploid, while 57 exhibited whole-genome doubling (WGD; 68.7%). Biallelic inactivation of CDKN2A/2B was common, primarily via homozygous deletion (22/83, 26.5%). Additionally, chromothripsis-like events identified in 33 tumors (39.8%), and high-level focal amplifications( > 10 copies gain) of oncogenic drivers, including EGFR, CDK4, ERBB2, MET, MDM2, MYC and CCNE1, were observed in 30 cases (36.1%). Ongoing analyses integrate transcriptomic and single-cell data to further expand these findings. Conclusions: Comprehensive whole-genome profiling reveals chromosomal instability as a prominent genomic feature of lung cancer brain metastases, supporting its potential role in shaping brain-specific tumor evolution and inter-metastatic heterogeneity, and providing a rational foundation for future biomarker development and clinical practice.