TY - JOUR
T1 - Plasma cell-free DNA variant analysis compared with methylated DNA analysis in renal cell carcinoma
AU - Lasseter, Kathryn
AU - Nassar, Amin H.
AU - Hamieh, Lana
AU - Berchuck, Jacob E.
AU - Nuzzo, Pier Vitale
AU - Korthauer, Keegan
AU - Shinagare, Atul B.
AU - Ogorek, Barbara
AU - McKay, Rana
AU - Thorner, Aaron R.
AU - Lee, Gwo Shu Mary
AU - Braun, David A.
AU - Bhatt, Rupal S.
AU - Freedman, Matthew
AU - Choueiri, Toni K.
AU - Kwiatkowski, David J.
N1 - Publisher Copyright:
© 2020, American College of Medical Genetics and Genomics.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
KW - clonal hematopoiesis
KW - genomic alterations
KW - massively parallel sequencing
KW - plasma cell-free DNA
KW - renal cell carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85084126790&partnerID=8YFLogxK
U2 - 10.1038/s41436-020-0801-x
DO - 10.1038/s41436-020-0801-x
M3 - Article
C2 - 32341571
AN - SCOPUS:85084126790
SN - 1098-3600
VL - 22
SP - 1366
EP - 1373
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 8
ER -