DNA-Repair Gene Variant Linked to Acute Graft-Versus-Host Disease in Pediatric Patients

Researchers co-led by C. R. S. Uppugunduri and P. Huezo-Diaz Curtis from the University of Geneva, discovered an association between DNA-repair gene variant MGMT rs10764881 (G>A) and grade II to IV acute graft-versus-host disease (aGVHD) in pediatric patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT).

More specifically, “children receiving busulfan-based myeloablative conditioning prior to allo-HCT and carrying MGMT rs10764881 variant are at increased risk of developing aGvHD [grade II to IV],” according to the authors. The study was published in The Pharmacogenomics Journal.

Investigators examined 51 variants within 17 DNA-repair genes for their association with grade II to IV aGvHD in 60 pediatric patients. In an exploratory cohort, the cumulative incidence of aGvHD was 12% (n = 7), and the variants MGMT rs10764881 (G>A) (odds ratios [OR] = 14.8) and EXO rs9350 (c.2270C>T) (OR = 11.5) were associated with aGvHD (95% CI 2.3–191.8 p = 0.001).

However, after further exploration in an extended cohort (n = 182) and in the presence of other clinical risk factors, only the MGMT variant remained significantly associated with aGvHD (adjusted hazard ratio [HR] = 2.05, 95% CI 1.06–3.94, p = 0.03) Researchers observed higher MGMT expression in GG carriers for rs10764881 and associated higher expression with higher IC50 of busulfan in lymphoblastoid cells.

Though the study was limited by small sample size in the exploratory cohort, the authors upheld the value of the results, stating that “understanding the effect of DNA-repair gene variation on normal tissues could also be beneficial for assessing the risk of [treatment-related toxicities].” They also called for further examination of MGMT rs10764881as a predictor of aGvHD.