Cell-Free DNA NGS Yields Low Detection in Metastatic ccRCC

By Leah Lawrence - Last Updated: August 2, 2022

Cell-free DNA-based next-generation sequencing (NGS) yielded low detection rates in patients with metastatic clear cell renal cell carcinoma (ccRCC), according to an analysis published in JCO Precision Oncology.

Researchers performed NGS of tumor DNA and plasma DNA using the MSK-IMPACT platform in 110 patients with metastatic ccRCC. They explored detection and concordance between blood and tumor tissue.

Tumor tissue testing identified 582 genetic alterations. Only 24 genomic alterations were found by MSK-IMPACT in cfDNA in seven of 110 patients (6%).

“We failed to identify genomic alterations in cfDNA in nearly all patients (94% of cohort),” the researchers wrote.

When the researchers performed manual cross-genotyping, 210 genomic alterations were detectable below threshold in 74 patients (67%).

Additionally, intrapatient concordance with tumor tissue was limited. This was true for several important alterations such as VHL (31.6%), PBRM1 (24.1%), and TP53 (52.9%).

“Chromosome 3p loss and VHL mutations are linchpin events in ccRCC pathogenesis and are typically retained during clonal evolution,” the researchers wrote. “We explored VHL mutation status and found expectedly genomic alterations detected in tumor tissue for most patients (89.1%). By automated calling of cfDNA-IMPACT, VHL mutations were detected in four patients (4.1%).”

The addition of expanded detection criteria and cross-genotyping increased detection to 32% but still left 68% of patients who had VHL mutations detected in tumor tissue, but not cfDNA.

“With maximally liberal detection thresholds and manual cross-genotyping, our detection rate and concordance for known tumor genomic alterations increase yet remain low, arguing against routine panel testing,” the researchers concluded.


Matched molecular profiling of cell-free DNA and tumor tissue in patients with advanced clear cell renal cell carcinoma