Wallen Zachary D, Tierno Marni, Schnettler Erica, Roos Alison, Green Michelle, Amoah Kobina, Previs Rebecca A, Hastings Stephanie, Pabla Sarabjot, Jensen Taylor J, Caveney Brian, Eisenberg Marcia, Sathyan Pratheesh, Ramkissoon Shakti H, Severson Eric A
Labcorp, Durham, NC, United States.
Illumina, San Diego, CA, United States.
Front Genet. 2025 May 2;16:1550706. doi: 10.3389/fgene.2025.1550706. eCollection 2025.
, , and gene fusions are rare oncogenic driver alterations found in diverse tumor types of adults and children. They are clinically important biomarkers as tumors harboring these genomic alterations have high response rates to targeted therapy. Routine testing for fusions and treatment with TRK inhibitors has been recommended in multiple tumor types; however, differences between testing technologies used for detecting fusions can result in variable likelihoods of identification.
To assess the prevalence of fusions in a real-world standard-of-care setting, we analyzed data from 19,591 FFPE samples encompassing 35 solid tumor types submitted for comprehensive genomic profiling (CGP) as part of routine clinical care. CGP testing included DNA hybrid-capture sequencing to detect small variants, copy number alterations, microsatellite instability (MSI), and tumor mutational burden (TMB). RNA hybrid-capture sequencing was concurrently performed to detect fusions and splice variants. Detected fusions were categorized as oncogenic, likely oncogenic, or variant of unknown significance (VUS) based on the fusion partner, orientation, and breakpoint position.
73 oncogenic or likely oncogenic fusions were identified in 69 unique tumor specimens across 19 tumor types for a total cohort prevalence of 0.35%. Tumor types with the highest fusion prevalence included glioblastoma (1.91%), small intestine (1.32%), and head and neck (0.95%) tumors with other solid tumor types ranging from 0.19% (uterine) to 0.63% (breast). We identified diverse intra and inter-chromosomal partner genes for fusions across all tumor types. Most fusions were detected in only one tumor specimen, though some recurrent fusions were noted with , , , , , , , and fusion partners. Most fusions were mutually exclusive from other genomic driver alterations, however, almost a third of tumor specimens (29%) contained at least one co-occurring genomic driver, which may affect treatment decisions.
The high prevalence of oncogenic and likely oncogenic fusions detected in our analysis suggests that RNA hybrid-capture-based sequencing for fusion detection is a highly sensitive method for identifying clinically meaningful known and novel fusions, which may be missed with other detection methods, directly impacting therapeutic options and patient outcomes.
NTRK、ROS1和ALK基因融合是在成人和儿童多种肿瘤类型中发现的罕见致癌驱动改变。它们是重要的临床生物标志物，因为携带这些基因组改变的肿瘤对靶向治疗有较高的反应率。在多种肿瘤类型中，已推荐对NTRK融合进行常规检测并用TRK抑制剂进行治疗；然而，用于检测NTRK融合的检测技术之间的差异可能导致识别的可能性不同。
为了评估在实际临床标准治疗环境中NTRK融合的患病率，我们分析了19591份福尔马林固定石蜡包埋（FFPE）样本的数据，这些样本涵盖35种实体瘤类型，作为常规临床护理的一部分提交进行综合基因组分析（CGP）。CGP检测包括DNA杂交捕获测序以检测小变异、拷贝数改变、微卫星不稳定性（MSI）和肿瘤突变负荷（TMB）。同时进行RNA杂交捕获测序以检测融合和剪接变异。根据融合伴侣、方向和断点位置，将检测到的NTRK融合分类为致癌、可能致癌或意义未明的变异（VUS）。
在19种肿瘤类型的69个独特肿瘤标本中鉴定出73种致癌或可能致癌的NTRK融合，总队列患病率为0.35%。NTRK融合患病率最高的肿瘤类型包括胶质母细胞瘤（1.91%）、小肠（1.32%）和头颈部（0.95%）肿瘤，其他实体瘤类型的患病率从0.19%（子宫）到0.63%（乳腺）不等。我们在所有肿瘤类型中鉴定出了不同的NTRK融合的染色体内和染色体间伴侣基因。大多数NTRK融合仅在一个肿瘤标本中检测到，不过也注意到一些与TPM3、TPR、ETV6、SPRY4、LMNA、TFG、CARS和STRN融合伴侣的复发性融合。大多数NTRK融合与其他基因组驱动改变相互排斥，然而，几乎三分之一的肿瘤标本（29%）包含至少一种同时发生的基因组驱动改变，这可能会影响治疗决策。
我们分析中检测到的致癌和可能致癌的NTRK融合的高患病率表明，基于RNA杂交捕获的融合检测测序是一种高度敏感的方法，可用于识别临床上有意义的已知和新型NTRK融合，而其他检测方法可能会遗漏这些融合，这直接影响治疗选择和患者预后。
