PO.CL01.06 · 临床研究
在一个大型中国肺癌队列中DNA与RNA NGS对FGFR2融合检测的差异
Differences in FGFR2 fusion detection between DNA and RNA NGS in a large Chinese lung cancer cohort
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摘要 Abstract
中文摘要
背景：成纤维细胞生长因子受体2（FGFR2）融合是非小细胞肺癌（NSCLC）中罕见的驱动基因改变，总体发生率约为0.02%。FGFR2融合断点通常发生在第17-19外显子内，并已鉴定出众多融合伙伴基因。虽然二代测序（NGS）是融合检测的主要方法，但在大规模队列中，基于DNA和基于RNA的NGS对FGFR2融合检测谱的差异仍未得到充分表征。
方法：本回顾性研究分析了一个由12,974份肿瘤样本组成的大型中国肺癌队列。其中，3,578份样本采用DNA-NGS进行融合检测，9,396份样本采用RNA-NGS检测。最终分析仅纳入分类为致病性或可能致病性的FGFR2融合。
结果：共鉴定出18例FGFR2融合事件，总体检出率为0.14%。患者队列以男性为主（72.22%），中位年龄65岁（范围：52-78岁）。组织学上，大多数病例诊断为肺腺癌（44.44%）和肺鳞状细胞癌（38.89%），3例病理未确定。所有FGFR2融合均以5'-3'重排为特征。DNA-NGS鉴定出5例FGFR2融合（0.14%），全部见于肺腺癌，融合伙伴异质，包括FGFR2-INPP5F、FGFR2-TACC2（非经典断点：第6外显子）、FGFR2-PCAT2、FGFR2-KCNH5，以及一例涉及FGFR2-NME9和NME9-FGFR2的复杂融合。同时，RNA-NGS检出13例FGFR2融合（0.14%），其伙伴分布与DNA-NGS不同：11例FGFR2-ATE1（84.62%）涉及非经典断点（第2/5/6/9外显子），以及FGFR2-BICC1和FGFR2-TACC2。所有FGFR2-ATE1融合患者均为男性，8例已明确病理的病例中有7例为肺鳞状细胞癌，提示潜在的富集现象。重要的是，FGFR2-ATE1融合缺乏FGFR2激酶结构域，且绝大多数（90.91%）支持性读长<100，提示表达水平低。这些特征意味着FGFR2-ATE1可能通过不依赖激酶的机制发挥致癌作用，此类融合不太可能对FGFR激酶抑制剂产生良好应答。对于非典型、低表达的融合转录本，其致病性需谨慎评估和重新分类。
结论：本研究揭示了DNA与RNA NGS之间不同的FGFR2融合检测模式。在为靶向治疗指导解读复杂或非典型融合时，建议整合DNA和RNA NGS的结果，以优化患者分层和治疗决策。
查看英文原文 English abstract
Background: Fibroblast growth factor receptor 2 (FGFR2) fusions are rare driver gene alterations in non-small cell lung cancer (NSCLC), with an overall incidence of approximately 0.02%. FGFR2 fusion breakpoints typically occur within exons 17-19, and numerous fusion partner genes have been identified. While next-generation sequencing (NGS) is the primary method for fusion detection, the differences in the detection spectrum between DNA- and RNA-based NGS for FGFR2 fusions remain inadequately characterized in large-scale cohorts.
Methods: This retrospective study analyzed a large Chinese lung cancer cohort comprising 12,974 tumor samples. Among these, 3,578 samples were tested by DNA-NGS for fusion detection, and 9,396 samples were tested using RNA-NGS. Only FGFR2 fusions classified as pathogenic or likely pathogenic were included in the final analysis.
Results: A total of 18 FGFR2 fusion events were identified, yielding an overall detection rate of 0.14%. The patient cohort was predominantly male (72.22%), with a median age of 65 years (range: 52-78). Histologically, most cases were diagnosed as lung adenocarcinoma (44.44%) and lung squamous cell carcinoma (38.89%), with 3 cases of undetermined pathology. All FGFR2 fusions were characterized by 5'-3' rearrangements. DNA-NGS identified 5 FGFR2 fusions (0.14%), all in lung adenocarcinoma, with heterogenous fusion partners including FGFR2-INPP5F, FGFR2-TACC2 (non-canonical breakpoints: exon 6), FGFR2-PCAT2, FGFR2-KCNH5, and one complex fusion involving FGFR2-NME9 and NME9-FGFR2. Meanwhile, RNA-NGS detected 13 FGFR2 fusions (0.14%), with a partner distribution distinct from DNA-NGS: 11 cases of FGFR2-ATE1 (84.62%) involving non-canonical breakpoints (exon2/5/6/9), as well as FGFR2-BICC1 and FGFR2-TACC2. All FGFR2-ATE1 fusion patients were male, and 7 of the 8 cases with specified pathology were lung squamous cell carcinomas, indicating a potential enrichment. Importantly, the FGFR2-ATE1 fusion lacked the FGFR2 kinase domain, and the vast majority (90.91%) had supporting reads <100, suggesting low expression levels. These features imply that FGFR2-ATE1 may exert oncogenic effects via kinase-independent mechanisms, and such fusions are unlikely to respond well to FGFR kinase inhibitors. The pathogenicity of atypical, low-expressed fusion transcripts requires cautious evaluation and reclassification.
Conclusions: This study reveals distinct FGFR2 fusion detection patterns between DNA and RNA NGS. When interpreting complex or atypical fusions for targeted therapy guidance, integrating results from both DNA and RNA NGS is recommended to optimize patient stratification and treatment decisions.
利益披露 Disclosure
W. Chen, None..
X. Yu, None..
L. Bai, None..
C. Wen, None..
W. Zhang, None..
W. Zou, None..
Z. Liu, None..
R. Sun, None..
M. Huang, None.