肺がんの脳転移に関与する遺伝子変化を特定～脳転移の予測・治療法の開発に期待～

2025-12-18

2025-12-18 国立がん研究センター

国立がん研究センターの研究グループは、日本人の肺がん患者約1,100人のがん組織解析から、肺がんの脳転移に深く関与する新たな遺伝子変化を特定した。解析の結果、15番染色体長腕の一部である15q15領域の欠失を持つ肺がんは、外科切除後に脳転移を起こす頻度が高く、その発生率は約3.9倍に上昇することが明らかになった。欠失領域にはMYCシグナルを抑制するMGA遺伝子が含まれ、15q15欠失によりMYCシグナルと酸化的リン酸化(OXPHOS)が活性化し、肺がん細胞が脳内環境で生存しやすくなると考えられた。さらに、15q15欠失を持つ肺がん細胞は、OXPHOS阻害薬に対して高い感受性を示した。本成果は、肺がん患者の脳転移リスク予測や、新たな治療法開発につながる重要な知見である。

<関連情報>

15q15染色体欠失は非小細胞肺癌における脳転移を促進する Chromosome 15q15 Deletion Drives Brain Metastasis in NSCLC

Jun Miyakoshi, MD ∙ Kouya Shiraishi, PhD ∙ Akifumi Mochizuki, MD, PhD ∙ … ∙ Shun-ichi Watanabe, MD, PhD ∙ Ryuji Hamamoto, PhD ∙ Takashi Kohno, PhD
Journal of Thoracic Oncology Published:November 7, 2025
DOI:https://doi.org/10.1016/j.jtho.2025.11.001

Abstract

Introduction

Brain metastasis (BM) is a devastating complication of NSCLC, particularly in NSCLC tumors harboring EGFR mutations. However, the genomic alterations driving BM remain poorly understood.

Methods

We analyzed three independent cohorts of resected NSCLCs from Asian patients, including 1081 primary tumor (PT) samples analyzed by whole-genome sequencing (WGS, discovery cohort, n = 180) or whole-exome sequencing (WES, validation cohort, n = 901), eight BM samples, and 17 matched primary–BM pairs analyzed by WGS (BM cohort). Furthermore, RNA sequencing of the available 172 samples in the validation cohort and drug sensitivity profiling using NSCLC cell lines were performed.

Results

In the discovery cohort, deletions of the 15q15 chromosomal segment were more enriched in PTs from patients with BM than in those without this deletion (73% versus 39%, p = 0.004). Cumulative BM incidence was significantly higher in PTs with the 15q15 deletion (subdistribution hazard ratio = 3.9, p = 0.008 [Fine–Gray competing risk analysis]), whereas metastases at other organ sites did not differ significantly. These findings were obtained using the validation cohort. The 15q15 deletions significantly co-occurred with EGFR mutations (p = 2.8 × 10^-7). In matched PT–BM pairs, the 15q15 deletion was detected exclusively in BMs in 46.7% of patients. The deleted region includes the MGA gene, encoding a suppressor of MYC signaling. Transcriptomic analysis revealed MYC signaling and oxidative phosphorylation (OXPHOS) activation in PTs from patients with BM. NSCLC cell lines harboring the 15q15 deletion were selectively sensitive to elesclomol, an OXPHOS inhibitor.