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

Kathryn Lasseter, Amin H. Nassar, Lana Hamieh, Jacob E. Berchuck, Pier Vitale Nuzzo, Keegan Korthauer, Atul B. Shinagare, Barbara Ogorek, Rana McKay, Aaron R. Thorner, Gwo Shu Mary Lee, David A. Braun, Rupal S. Bhatt, Matthew Freedman, Toni K. Choueiri, David J. Kwiatkowski

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish
Pages (from-to)1366-1373
Number of pages8
JournalGenetics in Medicine
Issue number8
StatePublished - Aug 1 2020


  • clonal hematopoiesis
  • genomic alterations
  • massively parallel sequencing
  • plasma cell-free DNA
  • renal cell carcinoma


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