Kathryn Lasseter1, Amin H Nassar1,2, Lana Hamieh1,2, Jacob E Berchuck2, Pier Vitale Nuzzo2, Matthew Freedman3, Toni K Choueiri4, David J Kwiatkowski5, Keegan Korthauer6, Atul B Shinagare7, Barbara Ogorek1, Rana McKay8, Aaron R Thorner2,9, Gwo-Shu Mary Lee2, David A Braun2, Rupal S Bhatt10. 1. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. freedman@broadinstitute.org. 4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Toni_Choueiri@dfci.harvard.edu. 5. Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. dk@rics.bwh.harvard.edu. 6. Department of Statistics, University of British Columbia, Vancouver, BC, USA. 7. Department of Radiology, Brigham and Women's Hospital/ Dana-Farber Cancer Institute, Boston, MA, USA. 8. Moores Cancer Center, UC San Diego Health, San Diego, CA, USA. 9. Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, USA. 10. Division of Hematology Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Abstract
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.
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.
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