Rare <i>TCF3</i> variants associated with pediatric B cell acute lymphoblastic leukemia

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. <i>IKZF1</i> and <i>PAX5</i>, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced <i>TCF3</i>, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children’s Cancer Study Group (TCCSG) were examined. As a <i>TCF3</i> gene-based evaluation, the numbers of rare deleterious germline <i>TCF3</i> sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a <i>TCF3</i> single-variant evaluation, the frequencies of rare deleterious germline <i>TCF3</i> sequence variants in patients with pediatric B-ALL were also compared with those in control data. <i>TCF3</i> gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, <i>TCF3</i> variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, <i>p</i> = 0.0006) and pediatric B-ALL development. <i>TCF3</i> variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.