Molecular insights: Detecting gene fusions offers new avenues for advanced cancer management

By Neha MathurReviewed by Lily Ramsey, LLMAug 8 2023

In a recent article published in the Biologics Journal, researchers examined de-identified clinical data to identify gene fusions by next-generation deoxy- and ribonucleic acids (DNA and RNA) sequencing to understand their relationship with observed pathologies in a diverse population of cancer patients.

Study: Precision Medicine in a Community Cancer Center: Pan-Cancer DNA/RNA Sequencing of Tumors Reveals Clinically Relevant Gene Fusions. Image Credit: luchschenF/Shutterstock.com

Background 

Advancements in sequencing technologies facilitate the detection of gene fusion events in relevant cancer genes among patients with solid tumors and or hematological malignancies, which is crucial for precision oncology programs.

Gene fusions, i.e., the formation of a hybrid gene through genomic rearrangements, are therapeutic targets of interest or prognostic, diagnostic, or therapeutic biomarkers that help physicians prescribe specific therapies to cancer patients, which help improve treatment outcomes.

About the study

In the present study, researchers analyzed formalin-fixed paraffin-embedded (FFPE) 4,415 samples derived from solid tumors of diverse cancer patients through two commercial labs in the USA between 2016 and 2022. A pathologist closely reviewed FFPE specimens to confirm the tumor size, content, and quality.

These samples had 20% tumor content for RNA sequencing, done on a targeted panel of 52 genes that potentially identified gene fusions and gene variant transcripts up to 2019, after which the team performed whole transcriptome sequencing (WTS) on these samples. 

Further, they evaluated additional biomarkers using a DNA-based next-generation sequencing (NSG) panel of 592 genes, which encompassed microsatellite instability (MSI) and tumor mutational burden (TMB), with subsequent transition to whole-exome sequencing (WES) post-2019. 

Before molecular testing, the team used manual microdissection techniques to achieve tumor enrichment of harvested targeted tissue. In addition, the team evaluated programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry (IHC). 

Furthermore, the researchers used OncoKB, a precision oncology knowledge base, to classify identified gene fusions into two groups, unclassified and known oncogenic gene fusions. 

Results

The most important finding of this study was that 9.5% of analyzed tumor samples had oncogenic gene fusions of clinical relevance. In contrast, the authors identified unclassified gene fusions in 25/4415, i.e., 0.57% of the analyzed samples. The cost of DNA sequencing has decreased exponentially in the past two decades.

When used in tandem with RNA sequencing, it is crucial for identifying unclassified oncogenic fusions, novel therapeutic targets and optimizing the efficacy of existing cancer treatments.

Moreover, the current study underlined the significance of including a wide variety of tumors, as even low-frequency fusions have pronounced functional effects on the likelihood of cancer development, growth, and drug sensitivity.

Of all the new oncogenic gene fusions identified in this study, bone morphogenetic protein receptor 1B (BMPR1B)-PDZ and LIM Domain 5 (PDLIM5) and in-frame nipped-B-like protein (NIPBL)-piezo type mechanosensitive ion channel component 1 (PIEZO1) fusions are described in detail below.

The role of BMPR1B gene fusions and their protein products in cancer biology remains unknown because, to date, standardized classification guidelines for inherited conditions arising from the loss of function gene fusions do not exist.

Expert panels are working on standardizing methods for identifying and documenting loss-of-function gene fusions, such as the BMPR1B-PDLIM5 fusion.

The NIPBL gene-encoded protein is an essential regulator of the cohesin complex function. Some recent studies have found that loss-of-function mutations in NIPBL and its overexpression promote cancer cell growth and survival.

Moreover, exon 8 of NIPBL is involved in the in-frame NIPBL-NACC1 fusion that characterizes a unique “cholangioblastic” variant of cholangiocarcinoma. 

Furthermore, a recent study showed NIBPL deficiency upregulates endogenous retroviruses and stimulates PD-L1 expression, a well-recognized cancer immune evasion mechanism. Together, these observations prompt researchers to explore NIPBL as a therapeutic target in cancer and its functions as an oncogene or tumor suppressor.

Conclusions

Given the lack of standardization in their discovery and validation, further research could help determine the functional consequences of the unclassified gene fusion events and their potential clinical relevance. It will infuse more confidence in the researchers reporting these events. 

Future clinical trials should include WES and whole-transcriptome-based tumor profiling to identify gene fusions that remained undetected by the panels used in the current study. It could also help identify novel tumor histologies or novel fusion events. 

Nonetheless, the study data and data from the suggested clinical trials could help clinicians in decision-making regarding cancer patient treatment and their inclusion in other cancer trials in the future.