Factors influencing background cell-free DNA levels: Implications for donor derived cell-free DNA assessment in transplant patients
Trudy McKanna1, Philippe Gauthier1, Alexey Aleshin1, Svetlana Shchegrova1, Ekaterina Kalashnikova1, Shruti Sharma1, Himanshu Sethi1, Raheleh Salari1, Ryan Swenerton1, Zachary P. Demko1, Bernhard Zimmermann1, Paul R. Billings1.
1Natera, Inc, San Carlos, CA, United States
Background: Precision medicine, allowing personalized immunosuppression optimization, may reduce organ rejection, especially in kidney transplant patients, where the rejection rate is ~10% in the first year post-transplant.1 Early detection of rejection and subsequent treatment in transplant patients may improve clinical outcomes.2 Donor-derived cell-free DNA (dd-cfDNA) in the plasma of transplant recipients has been used as a metric to determine graft injury due to immunologic rejection.2,3 Utilization of cfDNA as a biomarker is also clinical relevant in other disease conditions, such as cancers, stroke, autoimmune diseases and pregnancy related complications. Multiple clinical factors influence dd-cfDNA and background cfDNA levels. To better interpret the proportion of dd-cfDNA with respect to background cfDNA, we sought to understand the association of a number of factors, in over 1500 patient samples with early-stage cancer.
Methods: The impact of surgery/procedural trauma on the background cfDNA level was studied in early-stage cancer patients (n>1500) as well as healthy controls. cfDNA levels were quantified pre-surgery and post-surgery at various time points up to six weeks. For a subset of patients, regression analysis was performed to establish the relationship between total cfDNA levels with age and gender. Further subset analysis of the impact of concurrent medications, treatment-related adverse events, body mass index, and comorbidities on background cfDNA levels are currently underway.
Results and Discussion: Compared to the presurgical time point, plasma samples collected within the first four weeks post-surgery showed a significant increase in total cfDNA level (p<0.01). Background cfDNA level was found to be associated with increasing age but not gender.
Conclusion: cfDNA levels can be influenced by multiple factors including surgeries and patient age. Considering patient-related factors associated with background cfDNA may improve the clinician’s interpretation of dd-cfDNA results and patient outcomes.
 1. Wang JH et al. Adv Chronic Kidney Dis. 2016;23(5):281-6
 2. Knight SR et al. Transplantation 2019;103: 273–83
 3. Sigdel TK et al. J. Clin. Med. 2019, 8(1), 19; https://doi.org/10.3390/jcm8010019
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