lunes, 30 de junio de 2014

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection



Sci Transl Med
Vol. 6, Issue 241, p. 241ra77 
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007803
  • RESEARCH ARTICLE
GENOMICS

Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection

  1. Kiran K. Khush3,*
+Author Affiliations
  1. 1Departments of Bioengineering and Applied Physics, Stanford University, Stanford, CA 94305, USA.
  2. 2Howard Hughes Medical Institute, Stanford, CA 94305, USA.
  3. 3Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  4. 4Department of Pediatrics (Cardiology), Stanford University and the Stanford Cardiovascular Research Institute, Stanford, CA 94305, USA.
  5. 5Office of Heart Transplant Services, Kaiser Permanente Northern California, Santa Clara Medical Center, Santa Clara, CA 95051, USA.
  1. ↵*Corresponding author. E-mail: kiran@stanford.edu (K.K.K.); quake@stanford.edu (S.R.Q.)

Abstract

Monitoring allograft health is an important component of posttransplant therapy. Endomyocardial biopsy is the current gold standard for cardiac allograft monitoring but is an expensive and invasive procedure. Proof of principle of a universal, noninvasive diagnostic method based on high-throughput screening of circulating cell-free donor-derived DNA (cfdDNA) was recently demonstrated in a small retrospective cohort. We present the results of a prospective cohort study (65 patients, 565 samples) that tested the utility of cfdDNA in measuring acute rejection after heart transplantation. Circulating cell-free DNA was purified from plasma and sequenced (mean depth, 1.2 giga–base pairs) to quantify the fraction of cfdDNA. Through a comparison with endomyocardial biopsy results, we demonstrate that cfdDNA enables diagnosis of acute rejection after heart transplantation, with an area under the receiver operating characteristic curve of 0.83 and sensitivity and specificity that are comparable to the intrinsic performance of the biopsy itself. This noninvasive genome transplant dynamics approach is a powerful and informative method for routine monitoring of allograft health without incurring the risk, discomfort, and expense of an invasive biopsy.
Citation: I. De Vlaminck, H. A. Valantine, T. M. Snyder, C. Strehl, G. Cohen, H. Luikart, N. F. Neff, J. Okamoto, D. Bernstein, D. Weisshaar, S. R. Quake, K. K. Khush, Circulating Cell-Free DNA Enables Noninvasive Diagnosis of Heart Transplant Rejection. Sci. Transl. Med. 6, 241ra77 (2014).


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