Study Links Abnormal Gene Splicing to Treatment Response in Metastatic Kidney Cancer

Clinicians often trial immunotherapies or tyrosine kinase inhibitors without clear indicators of likely benefit. Dysregulated RNA processing is common in cancer and may reveal tumor vulnerabilities. A new study shows that a tumor’s “splicing burden”—the frequency of aberrant gene-splicing events—correlates with clinical response in metastatic kidney cancer.

City of Hope (Duarte, CA, USA) and the Translational Genomics Research Institute (TGen; Phoenix, AZ, USA) identified a significant association between splicing burden and treatment response in mRCC. Splicing burden refers to the accumulation of abnormal splice events within the tumor’s transcriptome. The investigators state that these transcriptomic errors may provide a predictive framework to personalize treatment selection.

The team performed RNA sequencing on tumor specimens from 101 patients with mRCC. By analyzing the transcriptome, they addressed a gap in current diagnostics, where few prognostic or predictive biomarkers exist. In their analysis, responders—those achieving obvious tumor shrinkage or stable disease for at least six months—exhibited hundreds of distinct splice events that differentiated them from non-responders.

Thirteen unique splice events were highly prevalent among patients who responded to immunotherapies and tyrosine kinase inhibitors. Tumors with a high splicing burden also showed signs of robust adaptive immune activation. The data suggest that splicing errors can generate new or malformed proteins that flag cancer cells for immune recognition, potentially explaining enhanced responsiveness to immune-based treatments.

The study, “Characterization of aberrant alternative splicing landscape in patients with mRCC,” was published in the Journal for ImmunoTherapy of Cancer. TGen is part of City of Hope. According to the authors, these findings could provide biomarkers to guide personalized therapy options and add to evidence that splicing events may serve as universal biomarkers across malignancies, including ovarian cancer and sarcomatoid renal cell carcinoma.

“There aren't many prognostic or predictive biomarkers in the kidney cancer space,” said Benjamin Mercier, B.S., a clinical research coordinator at City of Hope and first author on the study. “Our objective was to determine if we can identify predictive biomarkers from the transcriptome of these tumors.”

“By understanding how abnormal gene-splicing affects treatment, we're opening the door to innovative therapies that reshape patient outcomes and redefine what effective cancer treatment can look like,” said Sumanta Pal, M.D., co-director of the Kidney Cancer Program at City of Hope and a senior author on the study.

Related Links
City of Hope 
Translational Genomics Research Institute