Uncovering the diagnostic potential of seminal fluid beyond fertility: cfDNA methylation analysis for the detection of clinically significant prostate cancer
6 affiliations
- 1Fellow Health Inc., San Leandro, California, United States of America
- 2Dept. of Urology, University of California, San Francisco, California, United States of America
- 3Department of Clinical Research, Urology Clinics of North Texas, Dallas, Texas, United States of America
- 4Comprehensive Urology, Los Angeles, California, United States of America
- 5Integrated Medical Professionals, New York, New York, United States of America
- 6MidLantic Urology, Bala Cynwyd, Pennsylvania, United States of America
Abstract
Research on the potential use of seminal fluid as a liquid biopsy for prostate cancer detection has been limited due to challenges associated with acquisition of this bodily fluid in clinical studies. Here we sought to expand on our previous analysis, which demonstrated high levels of prostate-derived cell free DNA (cfDNA) in seminal fluid in presumed healthy individuals, to a much larger cohort that included participants with prostate cancer. A total of 279 men scheduled for prostate biopsy were enrolled over 4 months across 12 sites. Prior to their biopsy, participants mailed a seminal fluid sample collected at home to the laboratory, from which cfDNA was extracted and underwent methylation analysis. Consistent with our earlier study in healthy individuals, we observed an abundance of high molecular weight (HMW) cfDNA in all samples. Tissue-of-origin deconvolution revealed that granulocytes and sperm were the principal contributors to seminal fluid cfDNA, while prostate-derived cfDNA was present at abundances readily detectable with current technologies. The nucleosomal fraction was very pronounced in some but not all samples and was determined to be correlated with the relative sperm signal. The sperm signal was also observed to be associated with an increase in small insert sizes (< 125 bp) in the sequenced libraries. Unsupervised clustering revealed two distinct populations driven by the abundance of sperm and granulocytes. Since summarizing at the genomic region level confounded tissues of different origins, fragment-level DNA methylation features were used to characterize and quantify the prostate cancer related signal, and features associated with clinically significant prostate cancer were identified. This study expands on our previous work to further characterize seminal fluid and highlights its potential as a promising liquid biopsy medium for the detection and monitoring of clinically significant prostate cancer.
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BibTeX
@article{geis2026uncovering,
title = {{Uncovering the diagnostic potential of seminal fluid beyond fertility: cfDNA methylation analysis for the detection of clinically significant prostate cancer}},
author = {Jennifer Geis and James F. Smith and Tara Maddala and Greg Thoreson and Kiarash Michel and Jed Kaminetsky and Laurence Belkoff and Stephanie Huang and Bailey Griscom and James C. Hart and Shellie Bench and Hamisha Ardalani and Laura Rivas-Yepes and Daniel Civello and Kim M. Clark-Langone},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0356387},
url = {https://doi.org/10.1371/journal.pone.0356387},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Uncovering the diagnostic potential of seminal fluid beyond fertility: cfDNA methylation analysis for the detection of clinically significant prostate cancer
AU - Jennifer Geis
AU - James F. Smith
AU - Tara Maddala
AU - Greg Thoreson
AU - Kiarash Michel
AU - Jed Kaminetsky
AU - Laurence Belkoff
AU - Stephanie Huang
AU - Bailey Griscom
AU - James C. Hart
AU - Shellie Bench
AU - Hamisha Ardalani
AU - Laura Rivas-Yepes
AU - Daniel Civello
AU - Kim M. Clark-Langone
PY - 2026
DA - 2026/09/09
JO - PLOS One
DO - 10.1371/journal.pone.0356387
UR - https://doi.org/10.1371/journal.pone.0356387
AB - Research on the potential use of seminal fluid as a liquid biopsy for prostate cancer detection has been limited due to challenges associated with acquisition of this bodily fluid in clinical studies. Here we sought to expand on our previous analysis, which demonstrated high levels of prostate-derived cell free DNA (cfDNA) in seminal fluid in presumed healthy individuals, to a much larger cohort that included participants with prostate cancer. A total of 279 men scheduled for prostate biopsy were enrolled over 4 months across 12 sites. Prior to their biopsy, participants mailed a seminal fluid sample collected at home to the laboratory, from which cfDNA was extracted and underwent methylation analysis. Consistent with our earlier study in healthy individuals, we observed an abundance of high molecular weight (HMW) cfDNA in all samples. Tissue-of-origin deconvolution revealed that granulocytes and sperm were the principal contributors to seminal fluid cfDNA, while prostate-derived cfDNA was present at abundances readily detectable with current technologies. The nucleosomal fraction was very pronounced in some but not all samples and was determined to be correlated with the relative sperm signal. The sperm signal was also observed to be associated with an increase in small insert sizes (< 125 bp) in the sequenced libraries. Unsupervised clustering revealed two distinct populations driven by the abundance of sperm and granulocytes. Since summarizing at the genomic region level confounded tissues of different origins, fragment-level DNA methylation features were used to characterize and quantify the prostate cancer related signal, and features associated with clinically significant prostate cancer were identified. This study expands on our previous work to further characterize seminal fluid and highlights its potential as a promising liquid biopsy medium for the detection and monitoring of clinically significant prostate cancer.
SN - 1932-6203
ER -