PhD Scientific Days 2022

Pathology and Oncology III. (Poster discussion will take place in the Aula during the Coffee Break)

Genomic and transcriptomic profiling of pediatric acute lymphoblastic leukemia patients in Hungary

Text of the abstract

Advances in therapeutic strategies improved 5-year survival rates of patients with pediatric acute lymphoblastic leukemia (ALL), nevertheless, clinical management of relapse remains a challenge. Molecular characterization of leukemic blasts using the latest high-throughput sequencing technologies may help refine risk assessment and identify potential targets for therapeutic intervention.
In this study, we aimed at interrogating the genomic and transcriptomic landscape of Hungarian children with ALL in order to facilitate a more advanced, risk-adapted therapy selection and clinical decision-making.
Diagnostic samples of 144 B-ALL and 37 T-ALL patients were investigated. Copy number alterations (CNA) were screened with multiplex ligase-dependent probe amplification (MLPA) using SALSA MLPA P335, P327 and P383 probemixes. Somatic mutations were identified by targeted next-generation sequencing using a QIASeq Targeted DNA Custom Panel covering 102 recurrently altered, disease-relevant genes. Gene fusions were analyzed by the TruSight RNA Pan-Cancer Panel covering 1,385 genes.
CNAs were detected in 76% of B-ALL and 72% of T-ALL patients. The most frequently altered genes were CDKN2A/B (20%), PAX5 (19%) and ETV6 (18%) in B-ALL, whereas CKDN2A/B (58%), STIL (20%) and MLLT3 (20%) in T-ALL. 13% of B-ALL cases harbored IKZF1 deletion, four of which were classified in the IKZF1plus subgroup associated with very poor prognosis. Small genomic variants were most frequently observed in NRAS (21%), KRAS (19%), PTPN11 (13%) and NSD2 (10%) genes in B-ALL, NOTCH1 (58%), PHF6 (21%) and CCND3 (21%) in T-ALL. Notably, in 16% of B-ALL patients, mutations were detected in genes (FLT3, JAK2, IL7R, CRLF2) encoding actionable proteins. Gene fusions were identified in 48 % of B-ALL and 35 % of T-ALL patients, with ETV6-RUNX1, P2RY8-CRLF2, STIL-TAL1 and TCF3-PBX1 being the most frequent ones. Fusions characteristic of the BCR-ABL1-like subgroup were detected in 9% of cases with B-ALL.
NGS combined with MLPA is a fast, efficient, high-throughput method for genomic and transcriptomic profiling of children with ALL. Molecular profiling has identified actionable targets in 16% of patients, which may provide new opportunities for targeted therapeutical intervention.
Funding: FK20_134253 K21_137948 H2020-739593 EFOP-3.6.3-VEKOP-16-2017-00009 KDP-2020-1008491 TKP2021-EGA-24 TKP2021-NVA-15