Research Spotlight: Circulating tumor DNA enables sensitive detection of actionable gene fusions and rearrangements across cancer types

Kasi, P., et al. Circulating tumor DNA enables sensitive detection of actionable gene fusions and rearrangements across cancer types. Clinical Cancer Research. December 7, 2023.


Large-scale rearrangements are frequent events in cancer genomes, and rearrangements and fusions are therefore an important class of variants to detect when performing genomic profiling. However, these alterations present unique technical challenges for next-generation sequencing platforms. In addition, detecting rearrangements via liquid biopsy has been reported to be unreliable in blood samples with lower tumor DNA content (often <1% compared to tissue biopsy where tumor content is generally >20%).

Study details:

This study examines the landscape of rearrangements detected by liquid biopsy across different cancer types. Over 50,000 liquid biopsy samples from patients with solid tumors were profiled using FoundationOne®Liquid CDx, a hybrid-capture sequencing platform that queries 324 cancer-related genes. Tissue biopsies profiled using FoundationOne®CDx, which queries the same genes, were used as a comparator.

Although the prevalence of driver rearrangements was lower in liquid than tissue biopsies overall, the frequency of detection was comparable in liquid biopsy with a tumor fraction of ≥1%. Rearrangements in certain genes, including FGFR2, BRAF, RET, and ALK, were detected across cancer types, but tended to be clonal variants in some cancer types and potential acquired resistance variants in others.

Why this matters:

In contrast to some prior literature, this study reports detection of a wide variety of rearrangements using comprehensive genomic profiling of ctDNA using liquid biopsy, and distributions of fusion gene partners that resemble those of tissue biopsies. The prevalence of driver rearrangements in tissue and liquid biopsy was comparable when tumor fraction was ≥1%, indicating robust liquid biopsy sensitivity to detect fusions in samples with adequate ctDNA shed. Liquid biopsy presents a viable alternative when tissue biopsy is not available, and there may be less value in confirmatory testing when tumor fraction is ≥1%.

View the full publication in the Clinical Cancer Research.

December 15, 2023