Plasma cell-free DNA variant analysis compared with methylated DNA analysis in renal cell carcinoma

• Published in: Genetics in medicine Vol. 22; no. 8; pp. 1366 - 1373
• Main Authors: Lasseter, Kathryn, Nassar, Amin H., Hamieh, Lana, Berchuck, Jacob E., Nuzzo, Pier Vitale, Korthauer, Keegan, Shinagare, Atul B., Ogorek, Barbara, McKay, Rana, Thorner, Aaron R., Lee, Gwo-Shu Mary, Braun, David A., Bhatt, Rupal S., Freedman, Matthew, Choueiri, Toni K., Kwiatkowski, David J.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2020; Elsevier Limited
• Subjects: Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Cancer; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - genetics; Cell-Free Nucleic Acids - genetics; Deoxyribonucleic acid; DNA; DNA methylation; Genomes; Genomics; High-Throughput Nucleotide Sequencing; Human Genetics; Humans; Kidney cancer; Kidney Neoplasms - diagnosis; Kidney Neoplasms - genetics; Laboratory Medicine; Metastasis; Patients; Plasma; clonal hematopoiesis; renal cell carcinoma; plasma cell-free DNA; genomic alterations; massively parallel sequencing
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/s41436-020-0801-x

Purpose Plasma cell-free DNA (cfDNA) variant analysis is commonly used in many cancer subtypes. Cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) has shown high sensitivity for cancer detection. To date, studies have not compared the sensitivity of both methods in a single cancer subtype. Methods cfDNA from 40 metastatic RCC (mRCC) patients was subjected to targeted panel variant analysis. For 34 of 40, cfMeDIP-seq was also performed. A separate cohort of 38 mRCC patients were used in cfMeDIP-seq analysis to train an RCC classifier. Results cfDNA variant analysis detected 21 candidate variants in 11 of 40 mRCC patients (28%), after exclusion of 2 germline variants and 6 variants reflecting clonal hematopoiesis. Among 23 patients with parallel tumor sequencing, cfDNA analysis alone identified variants in 9 patients (39%), while cfDNA analysis focused on tumor sequencing variant findings improved the sensitivity to 52%. In 34 mRCC patients undergoing cfMeDIP-seq, cfDNA variant analysis identified variants in 7 (21%), while cfMeDIP-seq detected all mRCC cases (100% sensitivity) with 88% specificity in 34 control subjects. In 5 patients with cfDNA variants and serial samples, variant frequency correlated with response to therapy. Conclusion cfMeDIP-seq is significantly more sensitive for mRCC detection than cfDNA variant analysis. However, cfDNA variant analysis may be useful for monitoring response to therapy.