Audrey Bonaventure

Le but de cette thèse était d’analyser les associations entre plusieurs facteurs environnementaux (consommations maternelles de tabac, d’alcool et de boissons caféinées pendant la grossesse) et médicaux (antécédents d’asthme ou d’eczéma) et les leucémies aiguës de l’enfant, et d’étudier des polymorphismes génétiques susceptibles de modifier ces associations. Les analyses ont été réalisées à partir de l’étude cas-témoins nationale ESCALE réalisée en population générale en 2003 et 2004. Les données sur les antécédents médicaux et les consommations maternelles pendant la grossesse ont été recueillies au cours d’un entretien téléphonique standardisé des mères. Les polymorphismes génétiques d’intérêt ont été sélectionnés suivant une approche candidate sur leur fonctionnalité, dans des gènes impliqués dans le métabolisme du tabac (CYP1A1*2, CYP2E1*5, NQO1*2, EPHX1 et NAT2*5), de l’alcool (CYP2E1*5, ADH1C*2) et de la caféine (NAT2*5), et dans l’allergie (IL4, IL4R, IL10 et IL13). Les données génétiques ont été obtenues à partir de prélèvements de sang chez les cas et de salive chez les témoins, par génotypage de 370 000 SNPs chez les cas et sur puce à façon de 4 500 SNPs chez les témoins, complété par des imputations génotypiques lorsque les polymorphismes candidats n’étaient pas disponibles au génotypage. Au total, les données étaient disponibles pour 493 cas de leucémie aiguë et 442 témoins d’origine européenne.La consommation maternelle de café pendant la grossesse était positivement associée aux leucémies aiguës de l’enfant dans cette étude. Aucune association significative n’était observée avec le tabagisme maternel ou la consommation d’alcool pendant la grossesse. La présence de deux allèles NAT2*5 était associée aux leucémies aiguës lymphoblastiques (Odds Ratio OR=1.9 [1.3-2.7]), mais les analyses ne montraient pas d’association avec les autres polymorphismes des enzymes du métabolisme. Aucune interaction significative n’a été observée entre les polymorphismes candidats et le tabagisme maternel ou les consommations d’alcool ou de boissons caféinées pendant la grossesse. Cependant, les allèles candidats de CYP2E1, NQO1 et EPHX1, trois enzymes impliquées dans le métabolisme du benzène, semblaient interagir entre eux.Les allèles variants dans les gènes IL13, IL4, IL10 et IL4R n’étaient pas associés au risque de leucémie de l’enfant. Les antécédents d’asthme ou d’eczéma étaient plus fréquemment retrouvés chez les témoins que chez les cas (OR=0.7 [0.6-0.9]). Cette association inverse était essentiellement retrouvée chez les enfants porteurs d’un haplotype variant régulant l’expression de l’IL10 (p interaction=0.08) et porteurs de deux allèles de référence pour IL13-rs20541 (p interaction=0.06).En conclusion, ces résultats suggèrent un rôle de la consommation de café dans le risque de leucémie, déjà observé dans la précédente étude de l’équipe, qui devra être répliqué et approfondi. En revanche, aucune association n’a été observée avec la consommation maternelle de tabac ou d’alcool, même en tenant compte des polymorphismes génétiques candidats. L’interaction gène-gène des trois enzymes impliquées dans le métabolisme du benzène est intéressante et devra être explorée dans d’autres études. Enfin, l’association inverse entre le risque de leucémie aiguë et les antécédents d’asthme ou d’eczéma semble limitée aux enfants porteurs de certains polymorphismes des interleukines IL10 et IL13, ce qui pourrait refléter des mécanismes biologiques sous-jacents. Ces hypothèses pourront être testées d’autres études, et en particulier dans l’étude ESTELLE, récemment réalisée par l’équipe.

Background: Ependymoma is a malignancy of the neuroepithelium-derived ependyma that lines the spinal cord and ventricles of the brain, occurring most frequently in young children and older adults. Genetic susceptibility to ependymoma has proven difficult to assess due to disease rarity. Methods: We performed genome-wide association studies (GWAS) of 478 ependymoma patients and 4,841 disease-free controls of European ancestry. Ependymoma patients consisted of 117 children (<18 years old) with whole-genome sequencing (WGS), 142 children with genotyping, and 219 adults (≥18 years old) with genotyping. Genotyped samples were imputed using the 1,000 Genomes Project as the reference panel and underwent quality control filtering. The GWAS was performed separately by age group and technology (genotyped or WGS). GWAS variants were considered significant at P < 5 × 10−8. Results: Among pediatric subjects with WGS data, we identified a significant intronic variant in EDIL3 (rs149378, P = 1.9 × 10−8) and a nearly significant intronic variant in LHX4 (rs79008224, P = 7.2 × 10−8). In pediatric subjects with genotyped data, two significant intronic variants were detected: FAM149A (rs6852180, P = 1.8 × 10−8) and CYS1 (rs61052588, P = 3.0 × 10−8). Additionally, an intergenic variant near C1orf94 (rs1404350, P = 1.2 × 10−14) was highly significant. In genotyped adult subjects, a single variant was observed in KCNQ3 (rs79089725, P = 2.0 × 10−8). Conclusion: Our analysis represents one of the most extensive ependymoma-specific GWAS conducted to date. Several significant intronic variants were harbored in genes associated with cancer and neurological disease. Future studies are needed to investigate the role of these age-specific alterations in ependymoma pathogenesis.

Background: Maternal prenatal infections may affect fetal development, increasing the immunological vulnerability of offspring to childhood leukaemia (CL). The role of maternal infections in CL is unclear and might vary by subtype (lymphoblastic, ALL; myeloid, AML) or other characteristics. Understanding this potentially modifiable risk factor could inform prevention strategies. Methods: Seventeen hospital- and population-based case–control studies of children born in 1972–2019 within the Childhood Cancer and Leukemia International Consortium with self-questionnaires or health-registry data on maternal infection were included (13 638 cases; 26 870 controls). Meta-analyses assessed CL and maternal infection (overall, viral, bacterial, respiratory, influenza/cold, urinary, genital) stratified by subtype, infection timing, race and ethnicity, and diagnosis age. Results: The adjusted meta-analysis odds ratio (OR) for any maternal prenatal infection was 1.13 [95% confidence interval (CI) 0.91–1.40], with similar estimates for ALL and AML. Infection-specific estimates varied. ORs for first-trimester infections were highest for CL and ALL, but not AML, although all CIs contained one. We found modest risk differences between White and Hispanic/Latino children, most notably for CL diagnosed at <2 years (White children: OR 1.25, 95% CI 1.02–1.53; Hispanic/Latino children: OR 0.79, 95% CI 0.34–1.81, subgroup difference P = .05), with similar differences for viral and respiratory/influenza/cold infections. Conclusion: Although findings only modestly support an association between maternal prenatal infections and CL, some infections might increase the risk more markedly in young White children compared with Hispanic/Latino children. Risk patterns across race and ethnicity, type, and timing of maternal prenatal infection merit further investigation, as do studies with documented exposure information.

Often relying on mother's recollections of past events, the possible relationship between maternal illness in pregnancy and risk of malignancy in their offspring has long been a focus of research. Free from recall bias, this study of childhood cancer (0–14 years) examined these associations using data abstracted from mothers' primary‐care (1623 cases, 2521 controls) and obstetric (2721 cases, 5169 controls) records. Maternal infections and other illnesses in pregnancy were examined for any possible associations with childhood leukaemia, lymphoma, CNS or embryonal tumours using pooled information from the two medical record sources (2885 cases and 5499 controls), accounting for potential confounders. Maternal anaemia was associated with childhood acute myeloid leukaemia (AML) (odds ratio, OR = 2.07, 95%CI [1.40–3.08]). Anaemia during pregnancy was also recorded more frequently in the notes of mothers of children with medulloblastoma, retinoblastoma and embryonal rhabdomyosarcoma: ORs 2.36 [1.36–4.11], 1.83 [1.01–3.33] and 2.91 [1.64–5.16] respectively. Other associations included urinary tract infections (UTIs) and non‐Hodgkin lymphoma (NHL); preeclampsia and NHL; and polyhydramnios with both AML and NHL. No evidence was found to suggest that influenza during pregnancy impacted on childhood leukaemia risk. In conclusion, our findings are supportive of an association between maternal anaemia in pregnancy and childhood AML, and maternal anaemia and embryonal tumours; underscoring the need for further research exploring the potential causes and roles of iron and vitamin deficiencies. Due to small numbers and lack of corroborative evidence, the associations observed for UTIs, preeclampsia, and polyhydramnios must be treated cautiously.

Background: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results. Methods: We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. Results: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10−6 and less-stringent P-value of 3.5 × 10−5 accounting for the number of “independent” SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups. Conclusions: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. Impact: Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene–folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Background: Studies examining the potential impact of mothers’ health during pregnancy on the health of their offspring often rely on self-reported information gathered several years later. To assess the validity of this approach, we analysed data from a national case–control study of childhood cancer (diagnosed 40% higher. Decreasing with increasing time since pregnancy, sensitivity was ⩽40% for most infections and all drugs except ‘anti-epileptics and barbiturates’ (sensitivity 80% among controls). ORs associated with individual drug/disease categories that were based on self-reported data varied from 26% lower to 26% higher than those based on medical records; reporting differences between mothers of cases and controls were not systematically in the same direction. Conclusions: The findings highlight the scale of under-reporting and poor validity of questionnaire-based studies conducted several years after pregnancy. Future research using prospectively collected data should be encouraged to minimize measurement errors.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81‐0.96) or 7 to 12 months (OR 0.85, 0.79‐0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71‐0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63‐0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53‐0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B‐ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.