Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia

Abstract

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. IKZF1 and PAX5, 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 TCF3, 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 TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Keywords:

• Acute lymphoblastic leukemia
• child
• TCF3
• variant

Acknowledgments

We thank Ms. Mika Nagase for technical assistance.

Authors’ contributions

M.T. and U.Y.A designed the study; S.M. performed experiments; Y.A., K.K., Y.Y., D.H., Y.T., Y.N., M.Y., T.I., S.O., H.T., D.K., D.T., J.T., D.T., K.K., K.M., Y.S., J.F., D.M., Y.S., K.N., K.S., H.G., T.J., E.A.M., M.I., and S.M. collected the samples. A.M. and T.M. provided technical support and conceptual advice. All authors read and approved the final manuscript.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

Japan Agency for Medical Research and Development (AMED) 20ck0106467h0002; Japan Society for the Promotion of Science 19H03614.