Unearthing novel fusions as therapeutic targets in solid tumors using targeted RNA sequencing

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Oncogenic fusion genes are critical for cancer diagnosis and targeted therapy selection.
• Identifying and verifying novel fusion genes remains a significant challenge in cancer research.
• Targeted RNA sequencing offers a promising approach for comprehensive fusion gene detection.

Purpose of the Study:

• To evaluate the utility of targeted RNA sequencing in detecting known and unknown fusion genes in 165 tumor samples.
• To discover and characterize novel oncogenic fusion genes with potential therapeutic implications.
• To establish criteria for identifying oncogenic fusion genes in post-sequencing analysis.

Main Methods:

• Targeted RNA sequencing was performed on 165 tumor samples.
• Known and unknown fusion genes were identified using bioinformatics analysis.
• Additional criteria were applied to assess the oncogenic potential of novel fusions.
• Functional validation included assessing cell growth and drug response for specific fusions.

Main Results:

• Eight novel fusion genes with predicted oncogenicity were discovered.
• RAF1 fusion genes, specifically PTPRG-RAF1, were identified in two cases.
• PTPRG-RAF1 fusion was shown to increase cell growth.
• Dabrafenib, a BRAF inhibitor, effectively reduced the growth of cells expressing RAF1 fusions.

Conclusions:

• Targeted RNA panel sequencing is a valuable theragnostic tool for cancer.
• Established criteria aid in the identification of oncogenic fusion genes.
• The findings support the role of RAF1 fusions in cancer and highlight potential therapeutic strategies.