Abstract 1969: DNA methylation and mutation spectrum among pediatric acute lymphoblastic leukemia patients by Hispanic/Latinx ethnicity

Abstract

Abstract Previous studies, on mostly Non-Hispanic White (NHW), have identified genetic and epigenetic markers for pediatric acute lymphoblastic leukemia (ALL) relapse. Higher incidence rates and worse outcomes in Hispanic/Latinx (HSP) patients suggest that the genesis and progression of disease may vary by population. We compared methylation signatures and mutation spectrum between HSP and NHW ALL patients at diagnosis as well as by relapse status, defined as relapse within three years of diagnosis (early relapse) versus remission (>=4 years after diagnosis). Study participants included pediatric (1-19 years) patients in the Therapeutically Applicable Research to Generate Effective Treatments program. We included 26 HSP and 51 NHW patients with bone marrow samples at diagnosis including 11 HSP and 32 NHW patients with both diagnosis and relapse samples. The mean age at diagnosis for HSP was 8.8 years (standard deviation, sd=5.6) and NHW was 6.4, sd=4.9. The proportion of males (56%) was higher than females (44%). At diagnosis, the top methylated regions for the combined sample harbored the following genes: AB13, GNGT2, MAPK10, ARHGAP24, TEX264 and IQCF6 (all p<0.000001, all q<0.1) (all p<0.000005, all q<0.1). However, the top methylated regions for HSP did not overlap with those for NHW. For HSP, the top methylated regions harbored the following genes: ITPA, COX16, ADAM21, GALR1, MBP, DCLRE1A, PPP4R12 and IGSF11 (all p<0.000005, all q<0.1); while for NHW, the top methylated regions harbored the following genes: ARMC10, FBXL13, TEX264 and IQCF6 (all p<0.000002, all q<0.1). Similar results were observed for differentially methylated regions between diagnosis and relapse samples. The top regions for the overall sample harbored the following genes: RINT1, RPS16, PDE12, TDRKH, PLEKHG2, TPO, PXDN, DTNBP1, YTHDC1. For HSP, the top regions differentially methylated between diagnosis and relapse harbored SPOCK3, B3GALT6, KIAA1804, FAM201A, HEMK1 and CLRN1OS; while for NHW, the top regions differentially methylated between diagnosis and relapse harbored SRPK2, RINT1, TMPRSS11E, YTHDC1, GSTT1, SFTPB, GNLY, JARID2, DTNBP1, ZFP36 and RPS16. A comparison of mutation spectrum of frequently mutated genes in pediatric ALL revealed higher mutations in NRAS (12.5% vs 0%) and FLT3 (6.25% vs 0%), but not KRAS (12.5% vs 14.3%), for NHW (n=16) than HSP (n=14). Few of the candidate genes observed in HSP (ITPA, MBP, PPP4R12, and SPOCK3) have been previously implicated in leukemia. The findings suggest that the methylation signatures and mutation spectrum for HSP and NHW pediatric acute ALL patients might differ and further studies among HSP, a group with the highest prevalence of acute pediatric ALL, could potentially identify new genetic and epigenetic markers for acute pediatric ALL. Citation Format: Alexander Miller, Michael Considine, Leslie Cope, Ernest K. Amankwah. DNA methylation and mutation spectrum among pediatric acute lymphoblastic leukemia patients by Hispanic/Latinx ethnicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1969.