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Chromosome 15q15 Deletion Drives Brain Metastasis in NSCLC
Jun Miyakoshi1, Kouya Shiraishi2, Akifumi Mochizuki3
1Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan; Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan; Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Summary
Genomic deletions in the 15q15 region of non-small cell lung cancer (NSCLC) are linked to brain metastasis (BM). This 15q15 deletion promotes BM by activating MYC signaling and altering metabolism.
Area of Science:
- Oncology
- Genomics
- Cancer Metastasis
Background:
- Brain metastasis (BM) is a severe complication of non-small cell lung cancer (NSCLC), especially in patients with EGFR mutations.
- The specific genomic alterations driving BM in NSCLC are not well understood.
Purpose of the Study:
- To investigate the genomic drivers of brain metastasis in non-small cell lung cancer.
- To identify genetic alterations associated with increased risk of brain metastasis in NSCLC patients.
Main Methods:
- Analysis of three independent NSCLC cohorts (1081 primary tumors, 8 BM samples, 17 matched pairs) using whole-genome and whole-exome sequencing.
- RNA sequencing and drug sensitivity profiling of NSCLC cell lines were performed.
Main Results:
- 15q15 chromosomal deletions were significantly enriched in primary tumors of patients with BM (73% vs. 39%).
- PTs with 15q15 deletions showed a higher cumulative incidence of BM (SHR=3.9).
- The 15q15 deletion co-occurred with EGFR mutations and was found exclusively in BMs in 46.7% of matched pairs, implicating the MGA gene and MYC signaling.
Conclusions:
- The 15q15 deletion promotes brain metastasis development in NSCLC.
- Aberrant MYC signaling and metabolic reprogramming are key mechanisms driven by the 15q15 deletion in BM.
