Genomenon Provides Quick Answers On Fusion Genes

By Deborah Borfitz

July 10, 2019 | For decades, clinicians and researchers have been fascinated by fusion genes—genomic abnormalities that form when part of the DNA from one chromosome moves to another chromosome. Increasingly, they're also feeling overwhelmed by the hybrids. Well over 20,000 fusion genes have been documented since the first one was discovered in 1973 in chronic myelogenous leukemia, says Mark Kiel, MD, PhD, founder and chief science officer of Genomenon.

Hundreds of these fusion genes have been implicated in the development of cancer, making it easier than ever before to bring precision medicines to market and tailor treatments to individuals. What's not so easy is knowing if fusion events seen in patients are on that hit list and possibly treatable with a targeted therapeutic, says Kiel. Neither is manually poring through the published literature when crafting new study protocols.

This helps explain the growing popularity of the company's Mastermind suite of software tools, whose user base skyrocketed from 10 to over 3,000 clinicians in 100-plus countries over the past two years, and why dozens of pharmaceutical and biotechnology companies have licensed broader datasets produced by Genomenon, says Kiel. Mastermind is the most exhaustive genomic knowledge base in existence, built by indexing nearly seven million full-text genomic articles and 500,000 supplemental data sets. Machine learning and artificial intelligence are used to organize and present evidence from the literature and annotate it for both clinical effect and functional significance.

Mastermind is more inclusive of all documented fusions than either the Catalogue of Somatic Mutations in Cancer (COSMIC) and The Cancer Genome Atlas (TCGA), Kiel says, and also excludes fusion events that are of no clinical interest because they don't drive disease, are non-functional or merely artifacts of sequencing. Depending on how the data gets sliced, Mastermind will also produce 10 to 20 times more reference citations for each given gene pair than COSMIC, he adds, and they are "much more thoroughly annotated."

In a recent demo, Mastermind organized all the evidence (roughly 30,000 articles) on the 507 "bad actor" genes comprising the Illumina TruSight Fusion Gene Panel. It then compiled a list of the well-known fusion partners—numbering between one and 95—involved in 2,500 fusion events in those genes. The findings are contained in the newly released, nine-page "Genomenon Research Report: Fusion Genes of Clinical Significance in 2019."

Previously, Genomenon had focused its reports on variant-level information from small mutations, says Kiel. By popular demand, the latest report also highlights the bigger variants with known ties to cancer. Clinical labs that use the Illumina diagnostic tool in their workflow now have a ready reference for all other fusion genes outside the TruSight panel and, if seen in the genome of their patients, can learn which ones have been published before and if they cause disease and have a drug treatment.

Based solely on the number of articles, the 20 most common fusion partners represent 22.6% of the total fusion partners, says Kiel. The most "promiscuous partner," ALK (anaplastic lymphoma kinase), had nearly 100 unique fusion partners. "That in itself is five times more valid fusion partners than what's in the COSMIC database."

Role of Next-generation Sequencing

Next-generation sequencing (NGS), now performed more routinely because the cost has come down, has simplified the detection of fusion genes, notes Kiel. Fusion events were originally discovered via cytogenetic analysis using microscopes—and only if there was a big enough exchange of chromosomal material to be seen. "Cytogenetics requires a great deal of expertise and is pretty painstaking," he says. "You can only look at so many dozens of cells before you come to the end of the day."

In addition to accelerating workflow in the clinical lab, NGS assays pick up fusion events involving translocation of genetic material that is too small to be seen with a microscope, says Kiel. They also make possible larger-scale screening studies that discover novel fusions. "That's a virtuous circle of diagnosis and discovery that we are still seeing play out as reflected in the rate of novel fusions being published out in the literature."

Published articles on novel fusions have been on an upward trajectory for more than 30 years, says Kiel, as have those on fusion genes in general. Among newly published scientific articles in 2019, Mastermind identified 11 novel fusions involved in the genesis of multiple cancer types—several of which were found in a single patient—"suggesting that we are nowhere near the saturation point of discovering all fusion events that contribute to disease."

The discovery of a novel fusion in one patient could indicate a rare cancer, says Kiel, but it could also mean the sequencing assay has simply not been used enough to occasion more frequent detection. It's also possible that labs had identified the fusion event previously, but its clinical relevance had yet to be reported in the literature.

Fusion-targeted Drugs

At least two dozen drugs targeting gene fusions are now on the market, says Kiel, and many more are under development. The enthusiasm of researchers is due partly to the fact that "a fusion event is unequivocally a bad thing. ... It doesn't exist in nature and there is a pretty strong likelihood that it is driving a disease."

Additionally, the juxtaposition of previously separated genes "doesn't exist natively anywhere else in the body except in that cancer," he says. Small molecules that act on their unique fusion proteins can therefore be developed into highly targeted therapies that disrupt their function with minimal side effects.

When compounds showing promise in preliminary studies get married to a precisely defined genetic mechanism of disease like a fusion event, their likelihood of making it to market as a treatment can double if not triple—an "accelerated pace of drug development the likes of which we haven't seen in many decades," Kiel says. Since cancers like to reuse the same mechanisms of action in different tissue types, the commercialization of a fusion-targeted drug for one indication can also quickly expand to multiple other oncological conditions.

Gleevec (imatinib), the first fusion-targeted therapy to be FDA-approved in 2001, was featured on the cover of TIME magazine and coined the "magic bullet" that would cure cancer. It was an apt description, says Kiel. "Gleevec is a beautiful embodiment of precision medicine, from discovery of the fusion event to the ability to precisely diagnose the disease that it causes and perfectly target that fusion event with a precision therapeutic."