ARID5B, IKZF1 and Non-Genetic Factors in the Etiology of Childhood Acute Lymphoblastic Leukemia: The ESCALE Study

Jérémie Rudant (1) , Laurent Orsi (1) , Audrey Bonaventure (1) , Stéphanie Goujon-Bellec (1) , André Baruchel (2) , Arnaud Petit (3, 4) , Yves Bertrand (5, 6) , Brigitte Nelken (7, 8) , Marlène Pasquet (9) , Gérard Michel (10, 11) , Laure Saumet (12) , Pascal Chastagner (13) , Stéphane Ducassou (14) , Yves Réguerre (15) , Denis Hémon (1) , Jacqueline Clavel (1)

1 CRESS (U1153 / UMR_A_1125 / UMR_S_1153) - Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité
2 Service d'hématologie et immunologie pédiatrique
3 UMRS893 - Centre de Recherche Saint-Antoine
4 CHU Trousseau [APHP]
5 UCBL - Université Claude Bernard Lyon 1
6 Institut d’Hémato-Oncologie Pédiatrique
7 Université Lille Nord de France (COMUE)
8 Pôle Enfant
9 Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse]
10 AMU - Aix Marseille Université
11 Service d'hématologie et oncologie pédiatrique
12 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
13 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
14 Hôpital Pellegrin Tripode
15 Centre hospitalier Félix-Guyon [Saint-Denis, La Réunion]

Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95% CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95% CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95% CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.

Keywords: GENERAL-PRACTITIONER RECORDS; HEMATOPOIETIC MALIGNANCIES; INFECTIONS; CHILDREN; CANCER; RISK; VARIANTS; EPIGENETICS; PESTICIDES; EXPOSURE

Domains: Life Sciences [q-bio]; Cancer

Jérémie Rudant, Laurent Orsi, Audrey Bonaventure, Stéphanie Goujon-Bellec, André Baruchel, et al.. ARID5B, IKZF1 and Non-Genetic Factors in the Etiology of Childhood Acute Lymphoblastic Leukemia: The ESCALE Study. PLoS ONE, 2015, 10 (e0121348), ⟨10.1371/journal.pone.0121348⟩. ⟨hal-01217419⟩