Inherited genetic variant influences response to leukemia treatment for some children

September 2020 Science Eline Feenstra

Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on inter-patient variability in MRD. A new study published in Journal of National Cancer Institute looked at the role of specific genetic variants on treatment effectiveness and recurrence risk.

A genome-wide association study (GWAS) was performed on 2,597 children with high-risk ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863,370 single nucleotide polymorphisms (SNPs). Top variants were further evaluated in a validation cohort of 491 patients. The independent prognostic value of SNPs was determined in multivariable analyses. All statistical tests were two-sided.

GATA3 locus

In the GWAS, a genome-wide significant association was identified at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84, P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively).

In conclusion, the inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of genetic variants in upfront risk stratification in ALL.

Reference

Zhang H, Pak-Yin Liu A, Devidas M et al. Association of GATA3 polymorphisms with minimal residual disease and relapse risk in childhood acute lymphoblastic leukemia. J Natl Cancer Inst. 2020 Sep 7;djaa138. doi: 10.1093/jnci/djaa138.

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