Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors.

IF 4.1 2区医学 Q2 CELL BIOLOGY Molecular Cancer Research Pub Date : 2024-01-02 DOI:10.1158/1541-7786.MCR-23-0627

Kristyn Galbraith, Jonathan Serrano, Guomiao Shen, Ivy Tran, Cheyanne C Slocum, Courtney Ketchum, Zied Abdullaev, Rust Turakulov, Tejus Bale, Marc Ladanyi, Purvil Sukhadia, Michael Zaidinski, Kerry Mullaney, Sara DiNapoli, Benjamin L Liechty, Marissa Barbaro, Jeffrey C Allen, Sharon L Gardner, Jeffrey Wisoff, David Harter, Eveline Teresa Hidalgo, John G Golfinos, Daniel A Orringer, Kenneth Aldape, Jamal Benhamida, Kazimierz O Wrzeszczynski, George Jour, Matija Snuderl

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Abstract

DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions.

Implications: DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.

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罕见和多个并发基因融合对脑肿瘤诊断DNA甲基化分类器的影响。

DNA甲基化是中枢神经系统肿瘤诊断的重要分子检测方法。虽然一些融合定义了特定的脑肿瘤，但其他融合则发生在许多不同的诊断中。我们对219例具有全基因组DNA甲基化和RNA NGS的原发性中枢神经系统肿瘤进行了回顾性分析。将DNA甲基化分析结果与RNAseq检测的基因融合进行比较。我们检测到105个罕见的融合，涉及31个驱动基因，包括23个以前与脑肿瘤无关的融合。此外，我们还鉴定了6个多融合肿瘤。罕见的融合和多融合事件可以通过降低对结果的置信度来影响DNA甲基化的诊断准确性，例如BRAF、RAF或FGFR1融合，或者导致完全错配，例如NTRK、EWSR1、FGFR和ALK融合。含义：DNA甲基化特征需要在病理学的背景下进行解释，不一致的结果需要对新的和罕见的基因融合进行测试。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.