Genes are fundamental units of heredity, serving as instructions within our DNA that dictate various traits and bodily functions. Occasionally, two separate genes can join together to form a new, hybrid gene, a phenomenon known as gene fusion. This new gene can then produce an altered protein with different or entirely new functions compared to the original proteins. Understanding these fusions is a significant area of study in human health.
Understanding Gene Fusions
Gene fusions occur when segments of two distinct genes merge, creating a chimeric gene. This genetic alteration often arises from chromosomal rearrangements. Common types include translocations, where genetic material is exchanged between chromosomes, or inversions, where a segment of a chromosome is flipped. Deletions can also bring two genes into close proximity, leading to a fusion.
When a gene fusion forms, the resulting hybrid gene can produce an altered protein, also known as a fusion protein. This new protein may possess combined characteristics from both original proteins or entirely novel functions. For instance, if an active gene’s regulatory region fuses with another gene, it might cause the second gene to be overactive. This change in protein function or expression can have significant biological consequences.
Why Detecting Gene Fusions Matters
Detecting gene fusions is important because these altered genes can act as drivers in various diseases, particularly cancer. Many fusion genes lead to the production of abnormal proteins that promote uncontrolled cell growth and division. These are often referred to as “oncogenic drivers.”
The presence of specific gene fusions can indicate a particular type of cancer or predict how aggressive a disease might be. For example, the BCR-ABL1 fusion gene is a well-known oncogenic driver in chronic myeloid leukemia (CML). Identifying such fusions guides decisions about diagnosis, prognosis, and treatment strategies.
Methods for Gene Fusion Detection
Several techniques are employed to detect gene fusions. Fluorescence In Situ Hybridization (FISH) is a visual method that uses fluorescently labeled probes to bind to specific DNA or RNA sequences. Two differently colored probes are designed to target the two original gene segments. If a fusion is present, these two colors will co-localize under a microscope. FISH can detect specific known fusions and chromosomal rearrangements.
Reverse Transcription Polymerase Chain Reaction (RT-PCR) is a molecular method that detects fusion transcripts. This technique first converts RNA into DNA (reverse transcription) and then amplifies specific regions of this DNA. The presence of an amplified product of a specific size indicates a particular gene fusion. RT-PCR is sensitive and cost-effective for detecting specific known fusions.
Next-Generation Sequencing (NGS) analyzes large amounts of DNA or RNA simultaneously for comprehensive gene fusion detection. NGS can identify known and novel fusion events across the entire genome or transcriptome. Different NGS strategies, such as RNA sequencing (RNA-seq), are particularly effective for detecting fusion genes because they analyze the RNA transcripts. Bioinformatic tools then analyze the vast amount of sequencing data to pinpoint the exact fusion breakpoints.
Clinical Applications of Gene Fusion Detection
Detecting gene fusions has significant applications in clinical settings, impacting patient care from diagnosis to treatment. Identifying specific gene fusions can assist in the accurate diagnosis of certain disease subtypes, particularly in various cancers. For instance, the presence of specific fusions can confirm diagnoses in certain leukemias or solid tumors like lung cancers and sarcomas. This precision in diagnosis helps tailor subsequent management strategies.
Gene fusion detection also contributes to predicting disease prognosis, offering insights into the likely aggressiveness of a disease or a patient’s expected outcome. For example, certain fusions are associated with more aggressive forms of cancer, allowing clinicians to anticipate disease progression. This prognostic information aids in risk stratification and informs treatment intensity.
Perhaps one of the most impactful applications is guiding targeted therapy. Many fusion proteins are abnormal kinases that drive cancer growth and can be specifically inhibited by certain drugs. Identifying these “druggable” fusions, such as ALK, ROS1, or NTRK fusions, allows for the selection of therapies designed to block the activity of the aberrant fusion protein. This personalized approach often leads to more effective treatments with fewer side effects compared to traditional chemotherapy.