Fused DNA, commonly called a gene fusion, is a hybrid gene created when two separate genes that normally sit in different locations on your chromosomes get joined together. This produces a new, chimeric gene that contains the front portion of one gene and the back portion of another. The resulting gene can produce an abnormal protein that the body was never designed to make, and these proteins are key drivers of many types of cancer.
How Gene Fusions Form
Your chromosomes occasionally break and rearrange. Most of the time, repair mechanisms fix the damage accurately. But sometimes the repair goes wrong, and segments from different genes get stitched together. There are three main ways this happens.
Translocations are the most recognized mechanism. A piece of one chromosome breaks off and attaches to a different chromosome, bringing parts of two unrelated genes into contact. Inversions occur when a segment of a single chromosome flips orientation, potentially fusing genes that were facing opposite directions. Interstitial deletions happen when the DNA between two genes on the same chromosome gets removed entirely, collapsing the two genes into one continuous sequence. The end result is the same in all three cases: a brand-new hybrid gene that codes for a protein with altered or uncontrolled activity.
Importantly, a deletion and a translocation can sometimes produce the exact same fusion. For example, a deletion in a region of chromosome 1 can fuse a gene called LMNA with a gene called NTRK1. The identical fusion can also arise from a translocation between two copies of chromosome 1, as long as the breaks happen in the same spots.
Why Gene Fusions Matter in Cancer
Gene fusions are among the most powerful genetic drivers of cancer because the proteins they produce often get stuck in the “on” position. Normal cell-growth signals are tightly regulated, switching on and off as needed. A fusion protein can bypass those controls entirely, pushing cells to multiply without stopping and resist the normal signals that would trigger cell death.
Different fusions show up in different cancer types. The most common is TMPRSS2-ERG, found in roughly 38% of prostate adenocarcinomas. In lung adenocarcinoma, a fusion called EML4-ALK appears in about 5 to 8% of cases depending on how it’s measured, and it’s more common in people who have never smoked or smoked very little. Other notable fusions include CCDC6-RET in about 4% of thyroid cancers and FGFR2-BICC1 in nearly 6% of bile duct cancers.
The Philadelphia Chromosome: A Landmark Example
The most famous gene fusion in medicine involves chronic myeloid leukemia (CML). In the 1960s, researchers noticed an unusually short chromosome in the blood cells of CML patients. It turned out that pieces of chromosomes 9 and 22 had swapped places, creating what’s now called the Philadelphia chromosome. This swap fuses a gene called BCR on chromosome 22 with a gene called ABL1 on chromosome 9.
The resulting fusion protein acts as a permanently active enzyme that hijacks multiple growth and survival pathways inside white blood cells. It forces cells to keep dividing regardless of external signals, makes them resistant to programmed cell death, and lets them grow without the growth factors that normal cells depend on. The discovery of this fusion and its mechanism eventually led to one of the first targeted cancer therapies, transforming CML from a near-certain death sentence into a manageable chronic condition for many patients.
Fusions in Benign Tumors
Gene fusions aren’t exclusive to cancer. They also occur in several types of benign (non-cancerous) growths. Fusions involving a gene called HMGA2 have been found in lipomas (fatty lumps under the skin), uterine fibroids, cartilage-based growths called chondroid hamartomas, and endometrial polyps. These fusions typically drive the abnormal growth of the tumor but don’t trigger the aggressive, invasive behavior seen in malignant cancers. Their presence in benign conditions is a reminder that a gene fusion alone doesn’t automatically mean cancer, though certain fusions are far more dangerous than others.
How Doctors Detect Gene Fusions
Identifying a gene fusion in a tumor sample requires specialized laboratory testing, and no single method catches every fusion perfectly.
- Next-generation sequencing (NGS) is now considered the most efficient approach for clinical use. It can scan for many different fusions simultaneously in a single test and can confirm that the fusion actually produces a functional protein. Its main limitation is that it sometimes fails when the tissue sample yields poor-quality genetic material.
- FISH (fluorescence in situ hybridization) uses fluorescent probes to visually detect chromosome rearrangements under a microscope. It’s a well-established technique, but it can only look for one fusion at a time and struggles to detect very small rearrangements, since its resolution is limited to segments of about 100,000 to 200,000 DNA base pairs.
- RT-PCR amplifies specific RNA sequences to check whether a known fusion is being actively produced. It’s highly sensitive and cost-effective but, like FISH, only tests for one target per run.
In practice, many cancer centers use NGS as their primary screening tool and keep FISH or RT-PCR available as backup methods. FISH can sometimes catch fusions that NGS misses, particularly when tumor cells carrying the fusion make up only a small fraction of the sample.
Targeted Treatments for Fusion-Positive Cancers
The identification of gene fusions has opened the door to highly targeted therapies. Because fusion proteins often function as overactive enzymes called kinases, drugs that specifically block those enzymes can shut down the cancer’s primary growth signal.
One of the most significant developments is the concept of tumor-agnostic therapy, where a drug is approved based on the genetic alteration driving the cancer rather than where in the body the cancer started. Fusions involving the NTRK gene family are a prime example. These fusions appear at high rates in a handful of rare cancers (like infantile fibrosarcoma and secretory breast carcinoma) and at very low rates in more common cancers like those of the lung, pancreas, and colon. Drugs targeting the protein produced by NTRK fusions have shown impressive and lasting responses regardless of the patient’s age, tumor location, or which partner gene is involved. In June 2024, the FDA granted approval to a drug called repotrectinib for patients with NTRK fusion-positive solid tumors that had progressed after prior treatment or had no other satisfactory options.
This approach works because the fusion protein is the tumor’s central vulnerability. Block it, and the signals driving cell growth and survival collapse. In one reported case, a 61-year-old patient with advanced pancreatic cancer and liver metastases was found to carry an NTRK1 fusion after standard chemotherapy failed. Treatment with a TRK-targeting drug produced a partial tumor response and significantly improved quality of life.
Prognostic Implications
The presence of a gene fusion doesn’t just guide treatment decisions. It can also signal how aggressive a cancer is likely to be. A Dutch study of over 3,500 cancer patients found that those whose tumors carried NTRK fusions had a roughly 44% higher risk of death compared to patients without the fusion, though the finding came with a wide margin of uncertainty due to the small number of fusion-positive cases (just 24 out of 3,556). The fusions appeared across nine different tumor types, with NTRK3 and NTRK1 being the most commonly involved genes.
This kind of prognostic information matters when doctors and patients are weighing treatment intensity. It also underscores why comprehensive genomic testing early in a cancer diagnosis is increasingly seen as essential: finding a fusion can simultaneously explain why a tumor is behaving aggressively and reveal a specific vulnerability that targeted therapy can exploit.