Association study of candidate DNA-repair gene variants and acute graft versus host disease in pediatric patients receiving allogeneic hematopoietic stem-cell transplantation

Chakradhara Rao S Uppugunduri ,Simona Jurković Mlakar ,Maja Krajinović ,Jean‐Hugues Dalle ,Yves Chalandon ,Nicolas Waespe ,C Peters ,Patricia Huezo‐Diaz Curtis ,Fabienne Gumy‐Pause ,Christa E Nath ,Peter Bader ,Selim Corbacioglu ,Jaap Jan Boelens ,Tiago Nava ,R.g.m Bredius ,Peter J Shaw ,Vid Mlakar ,Mohamed Aziz Rezgui ,Fanette Bernard ,Yves Théorêt ,Henrique Bittencourt ,Marc Ansari

doi:10.1038/s41397-021-00251-7

Abstract

Acute Graft versus Host Disease (aGvHD) grades 2–4 occurs in 15–60% of pediatric patients undergoing allogeneic haematopoietic stem-cell transplantation (allo-HSCT). The collateral damage to normal tissue by conditioning regimens administered prior to allo-HSCT serve as an initial trigger for aGvHD. DNA-repair mechanisms may play an important role in mitigating this initial damage, and so the variants in corresponding DNA-repair protein-coding genes via affecting their quantity and/or function. We explored 51 variants within 17 DNA-repair genes for their association with aGvHD grades 2–4 in 60 pediatric patients. The cumulative incidence of aGvHD 2–4 was 12% (n = 7) in the exploratory cohort. MGMT rs10764881 (G>A) and EXO rs9350 (c.2270C>T) variants were associated with aGvHD 2–4 [Odds ratios = 14.8 (0 events out of 40 in rs10764881 GG group) and 11.5 (95% CI: 2.3–191.8), respectively, multiple testing corrected p ≤ 0.001]. Upon evaluation in an extended cohort (n = 182) with an incidence of aGvHD 2–4 of 22% (n = 40), only MGMT rs10764881 (G>A) remained significant (adjusted HR = 2.05 [95% CI: 1.06–3.94]; p = 0.03) in the presence of other clinical risk factors. Higher MGMT expression was seen in GG carriers for rs10764881 and was associated with higher IC50 of Busulfan in lymphoblastoid cells. MGMT rs10764881 carrier status could predict aGvHD occurrence in pediatric patients undergoing allo-HSCT.

Highlights

The most frequent immunological complication after allogeneic haematopoietic stem-cell transplantation is acute Graft versus Host Disease, occurring in 15–60% of transplants in children [1]
In patients receiving HSCT from HLA-identical siblings, the long-term survival rates with acute Graft versus Host Disease (aGvHD) grades III–IV are below 30% [2]. aGvHD begins with host normal tissue damage by the conditioning regimens that causes pro- and anti-inflammatory cytokine secretion which subsequently activate the host antigen presenting cells [3]
That effect is observed in tumor cells and in normal cells, the latter being linked to the treatment-related toxicities (TRTs) such as aGvHD

Summary

INTRODUCTION

The most frequent immunological complication after allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is acute Graft versus Host Disease (aGvHD), occurring in 15–60% of transplants in children [1]. Genetic polymorphisms within immunological pathways were described as risk factors [11], some of them in a pediatric MGMT mRNA expression pre- and post-busulfan exposure population [12]. Studies have implicated the role of genetic variants and altered expression of genes in the parental cells after BU exposure (mean IC50 = 117.68 μM ± 16.7 μM) (Supplementary Fig. 2). DNA-repair pathways BER and MMR in determining differences (p = 0.02) in the BU IC50 values between LCLs carrying treatment outcomes of AGs [16]. DNA-repair ability are at reduced risk of developing aGvHD by differences observed in expression levels between the short diminishing the activation of Phase 1 of the pathophysiology of plasmid construct containing alleles A and C of variant rs1625649 aGvHD. Strand break repair pathways were selected for the investigation [8, 13, 14, 16]

RESULTS

Findings

METHODS