Gene fusions are among the most important targets in precision oncology. They occur when part of one gene joins part of another, producing an abnormal protein that drives cancer growth. Fusions involving ALK, ROS1, RET, NTRK1, NTRK2, NTRK3, FGFR2 and NRG1 can be treated with highly effective targeted therapies.
The challenge of detecting fusions in DNA
Fusion breakpoints in DNA often fall within large introns, which can span many thousands of bases. DNA-based panels must cover these regions to find the breakpoint, and some introns are long or repetitive enough that a fusion can be missed.
The advantage of RNA
When a fusion gene is expressed, the introns are spliced out and the two partner genes are joined at an exon junction in the messenger RNA. RNA-based assays detect this junction directly. This makes fusion detection more sensitive, and also confirms that the fusion is expressed and therefore likely to be biologically active.
RNA also reveals changes that are difficult to see in DNA, such as MET exon 14 skipping in lung cancer, the EGFRvIII variant in gliomas and the AR-V7 splice variant in prostate cancer.
Combining DNA and RNA
Analysing DNA and RNA from the same sample gives a complete picture: DNA identifies point mutations, small insertions and deletions and copy number changes, while RNA identifies fusions and splice variants. Doing both in one test conserves tissue, which is often the limiting factor in small lung and pancreatic biopsies, and avoids the delay of sequential single-gene tests.
Clinical Impact
Fusion-driven cancers are often found in patients without traditional risk factors, such as never-smokers with lung cancer, and in younger patients. Missing a fusion can mean missing the most effective treatment available to the patient. For this reason, international guidelines for advanced non-small cell lung cancer recommend broad molecular profiling that includes fusion detection, and RNA-based testing is increasingly preferred for this purpose.