The TMPRSS2-ERG gene fusion represents a significant genetic alteration frequently observed in prostate cancer. This involves the merging of two distinct genes, leading to the creation of a new, altered gene product. Understanding this fusion is important because it is present in a substantial portion of prostate cancer cases and influences how the disease develops.
The TMPRSS2-ERG Fusion Gene
A fusion gene is a hybrid gene formed when parts of two previously separate genes combine. This genetic rearrangement can occur due to various chromosomal events, such as translocations, deletions, or inversions. In the case of TMPRSS2-ERG, the promoter region of the TMPRSS2 gene fuses with the coding sequence of the ERG gene.
The TMPRSS2 gene normally produces a protein called transmembrane protease, serine 2, which is an androgen-responsive enzyme found in prostate secretory epithelial cells. The ERG gene, on the other hand, is a member of the ETS (Erythroblast Transformation Specific) family of transcription factors. ETS family members play a role in regulating cell proliferation, differentiation, and other cellular processes. The fusion typically results in the overexpression of the ERG factor, driven by the TMPRSS2 promoter, which is regulated by androgens. The TMPRSS2 and ERG genes are located on chromosome 21, and their fusion often involves a deletion of the intervening genomic region.
Role in Prostate Cancer Development
The TMPRSS2-ERG fusion gene contributes to the initiation and progression of prostate cancer by acting as an oncogene. The fusion leads to the overexpression of the ERG protein, which then binds to target gene promoter regions, either activating or inhibiting them. This altered gene expression drives abnormal cell behavior.
Studies indicate that the TMPRSS2-ERG fusion promotes increased cellular invasion and migration. In laboratory settings, overexpression of ERG has been shown to enhance cellular migration and, in mouse models, increase subcutaneous tumor size and the number of bone metastases. The fusion also appears to engage components of the plasminogen activation pathway, which can mediate cellular invasion.
This gene fusion is a common molecular alteration in prostate cancer, identified in approximately 50% of prostate cancer cases in men of European ancestry. While its prevalence can vary by race or ethnic group, it is considered the predominant molecular subtype of prostate cancer. The TMPRSS2-ERG fusion is thought to occur early in prostate carcinogenesis, as evidenced by its homogeneous distribution in tumor foci and its identification, albeit rarely, in precursor lesions like high-grade prostatic intraepithelial neoplasia (HGPIN).
Identifying the Fusion Gene
Identifying the TMPRSS2-ERG fusion gene is valuable for understanding prostate cancer. Its detection can serve as a biomarker for diagnosis or prognosis. Several molecular techniques are employed to detect this specific genetic alteration.
One common method is Fluorescence In Situ Hybridization (FISH). FISH uses fluorescently labeled probes that bind to specific DNA sequences on chromosomes. For TMPRSS2-ERG, FISH probes can detect rearrangements between the two genes, including microdeletions on chromosome 21 that are associated with the fusion event. This technique is considered a standard for detecting gene fusion rearrangements.
Another approach is Reverse Transcription Polymerase Chain Reaction (RT-PCR). RT-PCR detects the RNA transcript produced from the fused gene. It can identify different variants of the TMPRSS2-ERG fusion transcript. More sensitive assays, such as branched DNA (bDNA) technology, have also been developed, which can detect fusion transcripts from very small amounts of RNA, potentially improving detection sensitivity compared to traditional RT-PCR. Next-generation sequencing (NGS) is also used to analyze the prevalence and genetic features of the fusion, offering a comprehensive look at genomic alterations.
Therapeutic Implications
Understanding the TMPRSS2-ERG gene fusion has opened new possibilities for targeted therapies in prostate cancer, aligning with precision medicine, which aims to deliver the right treatment by targeting specific molecular alterations in a patient’s cancer. Since the TMPRSS2-ERG fusion is a driver of tumor progression in a significant subset of prostate cancers, it represents an attractive therapeutic target.
One strategy involves developing drugs that specifically inhibit the activity of the ERG protein, which is overexpressed due to the fusion. Researchers are exploring various approaches, including small molecules like ERGi-USU, which has shown selective inhibition of ERG-positive cancer cell growth without significantly affecting normal cells. This compound works by inhibiting RIOK2, a kinase involved in ribosome biogenesis, leading to ribosomal stress in cancer cells.
Other potential strategies include peptidomimetic inhibitors that bind to the ERG protein’s DNA-binding domain, disrupting its interactions with DNA and other proteins, and promoting its degradation. Efforts are also focused on preventing the fusion event itself or targeting downstream pathways activated by the fused gene. The development of ERG-targeted drugs offers a promising precision medicine approach for patients with TMPRSS2-ERG fusion-positive prostate cancer.