Sixteen splice variants were identified as potential biomarkers for clear cell renal cell carcinoma in a new study published in European Urology and led by researchers at Moffitt Cancer Center. The team also described a tool to indicate which patients are at high risk of poor outcomes based on their biomarker expression.
“These results suggest that altered splicing variants may play an important role in the development of clear cell renal cell carcinoma and represent biomarkers for patient outcomes,” explained Brandon Manley, MD, study author and assistant member of Moffitt’s Department of Genitourinary Oncology. “Future studies are needed to clarify the mechanistic roles of aberrant splicing variants, implications in predicting response to systemic treatment and utility as a biomarker of disease detection, recurrence or metastasis.”
Kidney cancer accounts for only 4% of all cancers in the United States. However, its incidence has more than doubled since 1975, with the most common type being clear cell renal cell carcinoma. While outcomes of patients have been improving due to new treatment options, the five-year survival rate of patients is 50% to 69% and even less for patients with metastatic disease. Recent research suggests that renal cell carcinomas are heterogeneous cancers and comprise at least ten subtypes.
Clear cell renal cell carcinoma develops due to different types of genetic mutations, including alterations that are inherited and those that develop sporadically. But none of these mutations have been able to be used to develop effective therapeutics.
To help better understand the key molecular processes that contribute to clear cell renal cell carcinoma development, the Moffitt researchers began studying alternative messenger RNA (mRNA) splicing variants to determine if they are altered in this disease and if the variants could be used as biomarkers for patient outcomes.
They used a novel screening process that started with cancer cell line data followed by patient data to identify splicing variants that are enriched in patients. They identified 16 key splicing variants that were altered in patients with clear cell renal cell carcinoma, several of which were associated with disease biology and outcomes. The team also determined that several splice variants were associated with altered DNA modification patterns.
They used this information to create a survival risk tool based on the combined expression levels of five of the splice variants. Expression of RNASET2 and FGD1 was associated with poor outcomes, while expression of PDZD2, COBLL1 and PTPN14 was associated with better outcomes. The tool was able to stratify patients according to low, intermediate and high risk of overall and cancer-specific survival.
Next, they further analyzed protein expression patterns in clear cell renal cell carcinoma tumor samples and discovered that several proteins responsible for gene splicing had altered expression and protein modification patterns in the high-risk patient group.
“The discovery of kidney cancer-specific splicing variants may facilitate development of a blood-based liquid biopsy assay to better manage patients with the disease. We are testing whether these RNA splicing variants are also detectable in the blood of the patients with clear cell renal cell carcinoma. If successful, we will develop a highly sensitive blood-based method for early diagnosis of this disease.” said Liang Wang, MD, PhD, study author and senior member of the Department of Genitourinary Oncology.
He added that, “This noninvasive method may also be used to monitor disease progression and even predict treatment responses.”
