Association between genetic variants in the base excision repair pathway and outcomes after hematopoietic cell transplantations.
Alkylating agents with or without ionizing radiation are frequently used in pretransplant conditioning regimens. Damage induced by these agents is commonly repaired by the base excision repair (BER) pathway. Hence, we hypothesized that genetic polymorphisms in the BER pathway will be associated with posthematopoietic cell transplant (HCT) outcomes. We evaluated the association between single nucleotide polymorphisms (SNPs) (n = 179) in the BER pathway with treatment-related mortality (TRM) at 1 year and disease relapse in a cohort of 470 recipients who underwent allogeneic HCT for treatment of hematologic malignancies at the University of Minnesota. After adjustment for age at transplant, donor type, race, and conditioning regimen, 4 SNPs in OGGI, LIG3, and MUTYH genes (rs159153, rs3135974, rs3219463, and rs3219476) were associated with increased risk of TRM, whereas 2 SNPs in the TDG gene (rs167715 and rs2374327) were associated with decreased risk of TRM at 1 year (P <or= .01). Patients with increasing numbers of deleterious alleles in the BER pathway showed a higher cumulative incidence of TRM at 1 year (51% for >or=4 deleterious alleles versus 14% for <or=1 deleterious allele; P < .001). One SNP, rs3135974, in the LIG3 gene, was associated with decreased risk of disease relapse (P < .001) post-HCT. These findings suggest that SNPs in the BER pathway can be used as genetic biomarkers to predict individuals at high risk for TRM and disease relapse. Modulation of pretransplant conditioning may alter risk in these patients.
Thyagarajan
Bharat
B
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA. thya0003@umn.edu
Lindgren
Bruce
B
Basu
Saonli
S
Nagaraj
Sriharsha
S
Gross
Myron D
MD
Weisdorf
Daniel J
DJ
Arora
Mukta
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004260:DNA Repair; D020022:Genetic Predisposition to Disease; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult