Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China.
Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, Canada.
Cancer. 2019 Oct 15;125(20):3535-3544. doi: 10.1002/cncr.32372. Epub 2019 Jul 9.
Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions.
Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes.
Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so.
These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs.
脑转移瘤（BMs）患者预后较差，治疗选择有限。肺癌是最常见的原发性恶性肿瘤，导致 BMs；因此，了解增加 BM 风险的分子机制对于确定治疗靶点和开发有效干预措施至关重要。
回顾性研究了 61 例接受原发性非小细胞肺癌（NSCLC）和 BMs 手术切除的患者。对原发性 NSCLC 和匹配的 BMs 进行了靶向 416 个癌症相关基因的下一代测序综合基因组分析。
主要驱动基因突变，包括 EGFR、KRAS、TP53 和 ALK，在原发性 NSCLC 和匹配的 BMs 之间高度一致（>80%），而不一致表明 NSCLC BMs 的独特基因组进化和致癌机制。BMs 还显示出比原发性 NSCLC 更高水平的拷贝数变异。此外，PI3K 信号通路编码基因 CDK4/CCND1、CDKN2A/2B 和的改变在 BMs 中富集，这表明它们与增加的转移风险相关。事实上，在原发性 NSCLC 中具有激活的 PI3K 信号的患者 BM 无复发生存期明显更短（风险比，8.49；P=0.0005）。此外，TP53 突变或通过 CTNNB1、APC 和 AXIN2 突变激活的 WNT 通路趋势表明 BM 无复发生存期较短，但无统计学意义。
这些发现深入了解了原发性 NSCLC 和匹配的 BMs 的基因组复杂性和异质性。本研究强调了 PI3K 信号与 NSCLC 患者转移风险增加的显著相关性，并确定了在 NSCLC BMs 中富集的基因组改变，这些改变可能作为治疗 NSCLC BMs 患者的预后标志物和潜在治疗靶点。
