BRAF 融合定义了非小细胞肺癌的治疗脆弱性和酪氨酸激酶抑制剂耐药
BRAF fusions define therapeutic vulnerability and tyrosine kinase inhibitor resistance in non-small cell lung cancer.
作者
作者单位
- Department of Pathology, Zunyi Medical University Affiliated Hospital, Zunyi 563000, China.
- Department of Respiratory and Critical Care Medicine, Chongqing University Affiliated Three Gorges Hospital, Chongqing 404500, China.
- Department of Thoracic Surgery, Yan'an Affiliated Hospital of Kunming Medical University, Kunming 650051, China.
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing 210032, China.
- Department of Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, Changsha 410013, China. Electronic address: jiangyuan@hnca.org.cn.
- Department of Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, Changsha 410013, China. Electronic address: denghongyu@hnca.org.cn.
- Department of Clinical Laboratory, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University and Hunan Cancer Hospital, Changsha 410013, China. Electronic address: tangfqhnca@163.com.
摘要
中文
BRAF 融合是非小细胞肺癌（NSCLC）中罕见但临床相关的致癌事件，但其分子特征和最佳管理仍不清楚。我们回顾性分析了 97 例携带保留激酶结构域的 BRAF 融合的 NSCLC 患者，分为从头（N = 43）和获得性（N = 54）两组。比较了各亚组和对照驱动基因队列的临床和基因组特征。我们鉴定了 104 个 BRAF 融合，涉及 53 个独特伙伴基因，其中 29 个是新型的。常见伙伴包括 AGK（12.5%）、IGR（11.5%）、ZC3HAV1（7.7%）、TRIM24（5.8%）和 MKRN1（5.8%）。IGR 和 DTNB 在从头病例中更常见，而 AGK-BRAF 融合在获得性病例中占主导。在从头病例中，65.1% 缺乏共存的驱动基因。ZNF703 突变和 NRF2 通路改变在仅 BRAF 融合肿瘤中反复富集，而 CTNNB1 和 NKX2-1 突变相对于 ALK 重排病例富集。与其他驱动基因共存的 BRAF 融合显示 KMT2C 和 RTK-RAS 通路突变富集，TP53 突变相对于 RET 重排肿瘤富集。一位携带 TRIM24-BRAF 和 EGFR 外显子 19 缺失的患者从 MEK 和 EGFR 双重抑制中获得了临床获益。获得性 BRAF 融合在 EGFR-TKI 治疗后频繁检测到，在 63.0% 的病例中为主要改变。先前 EGFR-TKI 的中位无进展生存期与临床试验基准一致。NSCLC 中的 BRAF 融合具有分子异质性，从头和获得性病例具有不同的基因组景观。这些发现支持在疾病进展时进行重复全面的基因组分析，并提示通路导向的组合，如 MEK 加 EGFR 抑制，可能为特定患者提供个体化治疗选择。
English
BRAF fusions are rare but clinically relevant oncogenic events in non-small cell lung cancer (NSCLC), yet their molecular characteristics and optimal management remain unclear. We retrospectively analyzed 97 patients with NSCLC harboring kinase domain-retaining BRAF fusions, stratified into de novo (N = 43) and acquired (N = 54) groups. Clinical and genomic features were compared across subgroups and comparator driver cohorts. We identified 104 BRAF fusions involving 53 unique partner genes, 29 of which were novel. Common partners included AGK (12.5%), IGR (11.5%), ZC3HAV1 (7.7%), TRIM24 (5.8%), and MKRN1 (5.8%). IGR and DTNB were more commonly observed in de novo cases, whereas AGK-BRAF fusions predominated in acquired cases. Among de novo cases, 65.1% lacked co-occurring drivers. ZNF703 mutations and NRF2 pathway alterations were recurrently enriched in BRAF fusion-only tumors, while CTNNB1 and NKX2-1 mutations were enriched versus ALK-rearranged cases. BRAF fusions co-occurring with other drivers showed enrichment of KMT2C and RTK-RAS pathway mutations, with TP53 mutations enriched compared to RET-rearranged tumors. One patient with TRIM24-BRAF and EGFR exon 19 deletion derived clinical benefit from dual MEK and EGFR inhibition. Acquired BRAF fusions were frequently detected after EGFR-TKI therapy, representing the predominant alteration in 63.0% of cases. Median progression-free survival on prior EGFR-TKIs aligned with clinical trial benchmarks. BRAF fusions in NSCLC are molecularly heterogeneous, with distinct genomic landscapes between de novo and acquired cases. These findings support repeated comprehensive genomic profiling at progression and suggest that pathway-directed combinations, such as MEK plus EGFR inhibition, may offer individualized treatment options for selected patients.
分类与指标
- 研究类型
- 临床研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 5.3
- 新锐分区
- 2区