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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-05-1365.
Submitted May 9, 2002
Accepted August 5, 2002
A novel rapid single nucleotide polymorphism (SNP) based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation
Ephraim P Hochberg, David B Miklos, Donna Neuberg, Daniel A Eichner, Stephen P Mclaughlin, Alex Mattes-Ritz, Edwin P Alyea, Joseph H Antin, Robert J Soiffer, and Jerome Ritz*
Department of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
Department of Biostatistics, Dana Farber Cancer Institute, Boston, MA, USA
Department of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
* Corresponding author; email: jerome_ritz{at}dfci.harvard.edu.
A major endpoint of non-myeloablative hematopoietic stem cell transplantation (HSCT) is the attainment of either mixed chimerism or full donor hematopoiesis. Because the majority of human genetic disparity is generated by single nucleotide polymorphisms (SNPs) direct measurement of SNPs should provide a robust tool for the detection and quantitation of chimerism. Using Pyrosequencing, a rapid quantitative sequencing technology, we developed a SNP-based assay for hematopoietic chimerism. Based on 14 SNPs with high allele frequencies, we were able to identify at least 1 informative SNP locus in 55 patients with HLA-identical donors. The median number of informative SNPs in related pairs was 5 and in unrelated pairs was 8 (p<0.0001). Assessment of hematopoietic chimerism in post-transplant DNA was shown to be quantitative, accurate and highly reproducible. The presence of 5% donor cells was reliably detected in replicate assays. Compared to current measures of engraftment based on identification of STR, VNTR or microsatellite polymorphisms, this SNP-based method provides a more rapid and quantitative assessment of chimerism. A large panel of SNPs enhances the ability to identify an informative marker in almost all patient/donor pairs and also facilitates the simultaneous use of multiple markers to improve the statistical validity of chimerism measurements. The inclusion of SNPs that encode minor histocompatibility antigens or other genetic polymorphisms that may influence graft versus host disease or other transplant outcomes can provide additional clinically relevant data. SNP-based assessment of chimerism is a promising technique that will assist in the analysis of outcomes following transplantation.
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