1 Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark2 Functional Human Variation, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3 Department of Systems Biology, Technical University of Denmark4 Behavioral Phenomics, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark5 Metagenomics, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark6 Norwegian University of Science and Technology7 Copenhagen University Hospital
Objectives: To investigate association of host genomic variation and risk of infections during treatment for childhood acute lymphoblastic leukaemia (ALL). Methods: We explored association of 34 000 singlenucleotide polymorphisms (SNPs) related primarily to pharmacogenomics and immune function to risk of infections among 69 ALL patients on induction therapy. Results: Forty-eight (70%) patients experienced infectious events including 23 with positive blood cultures. Infectious events and positive blood cultures were associated significantly with 24 and 21 SNPs, respectively (P < 0.01). Classification and regression tree analysis demonstrated rs11033797 (OR51F1), rs2835265 (CBR1), rs28627172 (POLDIP3) and rs1129844 (CCL11) to be predictive of outcome. Among 61 patients for whom read-outs were available for all four SNPs, 40 of 41 patients with the worst SNP profile experienced at least one infectious event compared with five of the remaining 20 patients (Hazard ratio 9.0, 95% CI 3.4–23.5, which was unchanged after adjustments for neutrophil counts). Pathway analysis identified variations in ‘G-protein-coupled receptor (GPCR) downstream signalling’, ‘Bile acid and bile salt metabolism’ and ‘Class I MHC-mediated antigen processing and presentation’ to be highly predictive of infections. Conclusions: Our data indicate that host genomic profiling may predict the risk of infections during induction therapy. This may facilitate development of individualised supportive care.
European Journal of Haematology, 2014, Vol 92, Issue 4, p. 321-330
Adolescent; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Genetic Variation; Genomics; Humans; Infant; Infection; Male; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Risk; Treatment Outcome; Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae  human common female, male; human CBR1 gene [Hominidae] single-nucleotide polymorphism; human CCL11 gene [Hominidae] single-nucleotide polymorphism; human OR51F1 gene [Hominidae] single-nucleotide polymorphism; human POLDIP3 gene [Hominidae] single-nucleotide polymorphism; bile salt metabolism; 03502, Genetics - General; 03508, Genetics - Human; 14004, Digestive system - Physiology and biochemistry; 15006, Blood - Blood, lymphatic and reticuloendothelial pathologies; 24004, Neoplasms - Pathology, clinical aspects and systemic effects; 24010, Neoplasms - Blood and reticuloendothelial neoplasms; 34508, Immunology - Immunopathology, tissue immunology; 36001, Medical and clinical microbiology - General and methods; Clinical Immunology; Hematology; Molecular Genetics; Oncology; genome variation; infection Infection (MeSH) infectious disease; lymphoblastic leukemia Leukemia, Lymphocytic (MeSH) neoplastic disease, immune system disease, blood and lymphatic disease; Biochemistry and Molecular Biophysics; Human Medicine, Medical Sciences; bile acid digestive system; blood culture clinical techniques, diagnostic techniques; HEMATOLOGY; BURROWS-WHEELER TRANSFORM; ACUTE MYELOID-LEUKEMIA; PEDIATRIC-PATIENTS; READ ALIGNMENT; CHILDREN; CHEMOTHERAPY; THERAPY; ASSOCIATION; CANCER; POLYMORPHISMS; immunogenetics; single-nucleotide polymorphisms; pharmacogenetics; infection; childhood leukaemia; G protein coupled receptors; Childhood leukaemia; Immunogenetics; Pharmacogenetics; Single-nucleotide polymorphisms