TY - JOUR
T1 - Gene Expression Profiling Distinguishes a Molecular Signature for Grade 1B Mild Acute Cellular Rejection in Cardiac Allograft Recipients
AU - Bernstein, Daniel
AU - Williams, Gavin E.
AU - Eisen, Howard
AU - Mital, Seema
AU - Wohlgemuth, Jay G.
AU - Klingler, Tod M.
AU - Fang, Kenneth C.
AU - Deng, Mario C.
AU - Kobashigawa, Jon
PY - 2007/12
Y1 - 2007/12
N2 - Background: Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations. Methods: A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner. Results: Mean GE scores not only differentiated Grades ≥3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and ≥3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades ≥3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade ≥3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance. Conclusions: These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
AB - Background: Gene expression profiling distinguishes the absence or presence of moderate to severe grades of acute cellular rejection in cardiac allograft recipients using a 20-gene classifier. We explored the hypothesis that the rejection classifier also differentiates various forms of mild rejection and we performed sub-analyses based on time post-transplant and confirmatory pathology interpretations. Methods: A post hoc analysis of 265 CARGO study patients and 714 clinical encounters focused on the correlation of rejection classifier-derived gene expression (GE) scores for blood samples accompanying endomyocardial biopsies. Biopsy grades assigned by a study center pathologist (center) were re-interpreted by three pathologists (panel) in a blinded manner. Results: Mean GE scores not only differentiated Grades ≥3A from Grade 0 (p < 0.00001, center or panel), but also from Grades 1A or 2 (p < 0.05, center or panel), based on mild rejection sub-groups defined by the ISHLT 1990 grading system. In contrast, mean GE scores for Grades 1B and ≥3A were indistinguishable, using either center or panel interpretation. Sub-group analyses of encounters from 2 to 6 months or >6 months post-transplant showed similar results for the classifier's ability to discriminate moderate to severe rejection from Grades 1A and 2 mild rejection, but indistinguishable mean GE scores for Grades ≥3A and the Grade 1B sub-group. Of the classifier's 11 informative genes, expression of MIR and WDR40 showed statistically significant increases for both Grade 1B and Grade ≥3A rejection, while expression of PDCD1 or SEMA7A showed similar directional patterns without achieving statistical significance. Conclusions: These data demonstrate that GE scores discriminate moderate to severe rejection from Grades 1A and 2 mild rejection. However, a sub-group of mild rejection cases, defined as Grade 1B according to the 1990 grading system, share a molecular signature more consistent with moderate to severe rejection. The clinical relevance of these data remains to be defined.
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U2 - 10.1016/j.healun.2007.09.017
DO - 10.1016/j.healun.2007.09.017
M3 - Article
C2 - 18096478
AN - SCOPUS:37149043578
VL - 26
SP - 1270
EP - 1280
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
SN - 1053-2498
IS - 12
ER -