Modulation of the ETV6::RUNX1 Gene Fusion Prevalence in Newborns by Corticosteroid Use During Pregnancy

<i>ETV6::RUNX1</i>-positive pediatric acute lymphoblastic leukemia frequently has a prenatal origin and follows a two-hit model: a first somatic alteration leads to the formation of the oncogenic fusion gene <i>ETV6::RUNX1</i> and the generation of a preleukemic clone in utero. Secondary hits after birth are necessary to convert the preleukemic clone into clinically overt leukemia. However, prenatal factors triggering the first hit have not yet been determined. Here, we explore the influence of maternal factors during pregnancy on the prevalence of the <i>ETV6::RUNX1</i> fusion. To this end, we employed a nested interventional cohort study (IMPACT-BCN trial), including 1221 pregnancies (randomized into usual care, a Mediterranean diet, or mindfulness-based stress reduction) and determined the prevalence of the fusion gene in the DNA of cord blood samples at delivery (<i>n</i> = 741) using the state-of-the-art GIPFEL (genomic inverse PCR for exploration of ligated breakpoints) technique. A total of 6.5% (<i>n</i> = 48 of 741) of healthy newborns tested positive for <i>ETV6::RUNX1</i>. Our multiple regression analyses showed a trend toward lower <i>ETV6::RUNX1</i> prevalence in offspring of the high-adherence intervention groups. Strikingly, corticosteroid use for lung maturation during pregnancy was significantly associated with <i>ETV6::RUNX1</i> (adjusted OR 3.9, 95% CI 1.6-9.8) in 39 neonates, particularly if applied before 26 weeks of gestation (OR 7.7, 95% CI 1.08-50) or if betamethasone (OR 4.0, 95% CI 1.4-11.3) was used. Prenatal exposure to corticosteroids within a critical time window may therefore increase the risk of developing <i>ETV6::RUNX1</i>+ preleukemic clones and potentially leukemia after birth. Taken together, this study indicates that <i>ETV6::RUNX1</i> preleukemia prevalence may be modulated and potentially prevented.