Researchers have developed a new method to more accurately identify a subtype of kidney cancer that current gold-standard tests frequently miss. A study from the University of Michigan Health Rogel Cancer Center has found that analyzing the expression of a specific gene can uncover hidden genetic mutations in renal cell carcinoma, or RCC. This secondary analysis for tumors that initially test negative could significantly reduce underdiagnosis and guide more patients toward effective, personalized therapies.
The new findings address a critical gap in diagnosing MiTF family altered RCC, a type of kidney cancer driven by specific genetic rearrangements. The standard diagnostic tool, fluorescence in situ hybridization (FISH), can fail to detect these mutations in certain cases, leading to false-negative results. The Michigan research team discovered that tumors overexpressing the gene TRIM63, despite being FISH-negative, often harbored the very genetic alterations the initial test was designed to find. This insight provides a new molecular handle for pathologists, improving the chances of a correct diagnosis and ensuring patients have access to treatments tailored to their cancer’s specific genetic profile.
The Challenge of Diagnosing MiTF RCC
Renal cell carcinoma is a cancer originating in the lining of the kidney’s smallest tubes. Among its various forms, the subtype associated with the microphthalmia-associated transcription factor (MiTF) family presents a unique diagnostic puzzle. This cancer is characterized by specific changes to chromosomes, where parts of different genes break off and fuse together. The most common of these changes are rearrangements of the TFE3 and TFEB genes, which are known to drive the growth of these tumors.
Pathologists typically rely on a technique called fluorescence in situ hybridization to confirm a diagnosis of MiTF family altered RCC. The FISH assay works by applying fluorescent probes to samples of tumor tissue. These probes are designed to attach to specific DNA sequences on a chromosome. When a gene rearrangement has occurred, the fluorescent signals appear in an abnormal pattern under a microscope, giving clinicians a direct visual confirmation of the cancer-driving mutation. For years, this method has been considered the most reliable way to identify these specific cancers.
While FISH is invaluable, physicians have observed that it is not foolproof. Some kidney tumors show physical and cellular characteristics, or morphologies, that strongly suggest they are MiTF RCC, yet they return a negative result on the standard FISH test. This discrepancy creates a clinical dilemma, as a negative result might exclude a patient from receiving targeted therapies known to be effective against cancers with these specific gene fusions. The uncertainty pointed to a need for more sensitive or complementary diagnostic tools to capture the full scope of these complex cancers.
Overcoming the Limits of Standard Testing
The limitations of FISH testing stem from the complexity of the genetic rearrangements themselves. In some instances, the chromosomal changes are “cryptic,” meaning they are too small or located in unexpected regions for the standard probes to detect effectively. These subtle alterations can evade detection, leading to a false-negative result that conceals the true nature of the tumor. Such diagnostic blind spots can have serious consequences for patient care, as the opportunity for targeted intervention may be lost.
This diagnostic paradox prompted a deeper investigation by a team at the University of Michigan. Led by Dr. Rohit Mehra, the Godfrey Dorr Stobbe Research Professor of Translational Pathology, the researchers sought to understand the molecular underpinnings of these FISH-negative but morphologically suspicious tumors. They hypothesized that other genetic or protein markers could reveal the presence of MiTF family alterations that the primary FISH test had missed. Their work aimed to find a reliable biomarker that could serve as a secondary check, ensuring that complex cases were not misclassified.
A New Biomarker Comes to Light
In their search for an alternative identifier, Dr. Mehra’s team, in collaboration with the Michigan Center for Translational Pathology, focused on a gene known as TRIM63. While this gene had been previously linked to MiTF family altered RCC, it had not been systematically studied in cases that were negative by FISH. The researchers began to analyze these challenging tumor samples, looking for patterns in gene expression that could provide clues.
They discovered a strong and consistent link: many of the FISH-negative tumors that looked like MiTF RCC were found to have a significant overexpression of the TRIM63 gene. The TRIM63 gene itself is involved in a cellular process called ubiquitination, which helps regulate the degradation of proteins. Its heightened activity in these specific cancer cells suggested it could be a highly sensitive indicator of the underlying genetic mutations, even when those mutations were not visible to the standard FISH probes. This finding positioned TRIM63 as a promising new biomarker to help unmask these hard-to-diagnose cancers.
Validating the Enhanced Diagnostic Approach
To confirm their hypothesis, the research team employed a multi-pronged strategy combining traditional immunohistochemistry—a method used to detect specific proteins in tissue—with advanced genomic techniques. They systematically applied this combined approach to the perplexing FISH-negative tumor samples that showed high levels of TRIM63. The results provided powerful validation for their theory.
The study revealed that approximately 70% of the cases that were negative on the FISH test but positive for TRIM63 overexpression did, in fact, possess MiTF gene fusions. These advanced genomic analyses uncovered the cryptic or complex rearrangements that the initial test had missed, confirming the presence of the cancer-driving mutations. This high percentage underscored the clinical value of using TRIM63 as a secondary screening tool. It demonstrated that a significant number of MiTF RCC cases were being overlooked and that the new method could successfully identify them.
Expanding Treatment Opportunities
The ability to accurately classify these tumors has profound clinical significance. An accurate diagnosis is the first step toward effective, personalized cancer treatment. Therapies that target the specific pathways activated by MiTF gene fusions are available, but they are only prescribed to patients with a confirmed diagnosis. By correctly identifying the 70% of previously misidentified cases, the additional testing protocol opens the door for these patients to receive treatments that are better suited to their cancer’s genetic makeup.
This refined diagnostic pathway allows oncologists to move beyond a one-size-fits-all approach. By understanding the specific molecular drivers of a patient’s tumor, clinicians can make more informed decisions about treatment strategies, potentially improving outcomes and avoiding less effective therapies. The research marks a critical step forward in precision medicine for renal cell carcinoma, ensuring that the right patient gets the right treatment at the right time.
Future of Kidney Cancer Diagnosis
The findings from the University of Michigan team are set to influence the standard of care for diagnosing renal cell carcinoma. The identification of TRIM63 as a reliable biomarker for elusive MiTF gene fusions provides pathologists with a powerful new tool. The study makes a strong case for integrating immunohistochemical analysis of TRIM63 into the diagnostic workflow, particularly for tumors that appear suspicious but yield a negative result with conventional FISH assays.
This two-step process—initial FISH testing followed by TRIM63 analysis for negative cases—could become a new standard protocol in pathology labs. It offers a more comprehensive and accurate picture of the molecular landscape of these tumors, minimizing the risk of misdiagnosis. Further research may explore other potential biomarkers and continue to refine the classification of renal cancers, leading to an even deeper understanding of the disease.
Ultimately, this advancement contributes to the broader goal of making cancer treatment more precise and effective. By ensuring that diagnoses are as accurate as possible, researchers and clinicians can provide patients with renewed hope and a clearer path forward. The study highlights the importance of ongoing investigation into the molecular complexities of cancer, where uncovering a single gene’s role can create new possibilities for patients worldwide.