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Association between neonatal inflammatory markers and risk of infections before age 2 years.

ICD-10 codes for infections and ATC codes for antimicrobials.

It has been proposed that children with acute lymphoblastic leukemia (ALL) are born with a dysregulated immune function that together with postnatal environmental exposures causes childhood ALL. Despite its importance for the understanding of ALL etiology, this hypothesis has been inadequately explored. In a population-based case–control study, we measured the concentrations of 10 cytokines and other inflammatory markers on neonatal dried blood spots from 178 children who at ages 1 to 9 years were diagnosed with B-cell precursor ALL and 178 matched controls. Through linkage with Danish nationwide registers, we also assessed whether neonatal inflammatory markers were associated with previously demonstrated risk factors for childhood ALL. Children who developed B-cell precursor ALL had significantly lower neonatal concentrations of IL8, soluble IL6 receptor (sIL6R) α, TGFβ1, monocyte chemotactic protein (MCP)-1, and C-reactive protein (CRP) and higher concentrations of IL6, IL17, and IL18 compared with matched controls. Concentrations of IL10 were below the detection level for both patients and controls. Birth order (IL18 and CRP), gestational age (sIL6Rα, TGFβ1, and CRP), and sex (sIL6Rα, IL8, and CRP), but not maternal age, infections during pregnancy, birth weight nor mode of delivery were significantly associated with the neonatal concentrations of inflammatory markers. Our findings support the hypothesis that children who later develop B-cell precursor ALL are born with a dysregulated immune function.Significance: Children who develop acute lymphoblastic leukemia are immunologically distinct at birth and could potentially react abnormally to infections in early childhood. Cancer Res; 78(18); 5458–63. ©2018 AACR.

Neonatal inflammatory marker associations with maternal and child characteristics.

Intra and inter assay variations and correlation matrix of the inflammatory markers.

Variation in associations between prenatally initiated karyotypes and other kayotypes.

Purpose of the study: This study was aimed at identifying epigenome signature associated with risk of pediatric leukemia and uncovering molecular precursors of leukemia at birth in the blood of children before they develop the disease. Pediatric cancer is the leading cause of disease-related mortality in children and adolescents, with increasing incidence worldwide and lifelong sequelae in survivors. The most common form is leukemia, the causes of which are largely unknown. Growing evidence points to an origin in utero, when global redistribution of the epigenome modifications occurs driving tissue differentiation. Here, we sought to identify genome-wide differentially methylated genes at birth in newborns who later developed pediatric precursor B-cell ALL (pre-B ALL), compared with those who did not. Experimental procedures: Epigenome-wide DNA methylation was profiled in neonatal blood, with follow-up to pediatric pre-B ALL, using double-blinded analyses between prospective cohorts extending from birth to diagnosis and retrospective studies backtracking from clinical disease to birth. Validation was done using an independent technology and population (totaling 317 cases and 483 control) and complemented with pan-tissue methylation-stability (n=5,023 tissues; 30 types) and methylation-expression (n=2,294 tissues; 26 types) analyses. At diagnosis, methylation analysis was performed in leukemia tissues from pre-B ALL patients (n=644) with at least ten-year follow-up. Results: We found a limited number of loci (among which an imprinted tumor suppressor gene) as being significantly hypermethylated at birth in nested cases relative to controls in all tested populations, including European and Hispanic ancestries. Some DMRs were found to be stable over follow-up years after birth and across surrogate blood and target bone marrow tissues. Differential methylation was found to be associated with a change in gene expression and with worse pre-B ALL patient survival, supporting a functional and translational role for differential methylation. Conclusions: Our results provide proof-of-concept to detect at birth epigenetic alterations predisposing to childhood leukemia, reproducible in three continents and two ethnicities. DNA methylation alterations evident before diagnosis could be precursors of pediatric pre-B ALL development and actionable targets for risk assessment and prognosis. Citation Format: Akram Ghantous, Semira Gonseth Nusslé, Farah Nassar, Natalia Spitz, Alexei Novoloaca, Olga Krali, Ritu Roy, Shaobo Li, Maxime Caron, Lilys Lam, Peter Daniel Fransquet, John Casement, John Strathdee, Mark S. Pearce, Helen M. Hansen, Adam J. De Smith, Daniel Sinnett, Siri Eldevik Håberg, Jill McKay, Jessica Nordlund, Per Magnus, Terence Dwyer, Richard Saffery, Joseph Leo Wiemels, Monica Cheng Munthe-Kaas, Zdenko Herceg. Epigenome-wide DNA methylation alterations precede diagnosis since birth and affect prognosis of pediatric B-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB362.