Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response

Stefan-Hodorogea, Andreea; Radu, Letitia; Marcu, Andra; Serbanica, Andreea; Bica, Ana; Jercan, Cristina; Marcu, Ana; Jardan, Dumitru; Jardan, Cerasela; Calugaru, Onda; Dragomir, Mihaela; Popa, Codruta; Gheorghe, Anca; Vihta, Karina; Dima, Simona; Colita, Anca

doi:10.3390/ijms27104517

This is an early access version, the complete PDF, HTML, and XML versions will be available soon.

Open AccessArticle

Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response

by

Andreea Stefan-Hodorogea

^1,2,

Letitia Radu

^1,2,*

,

Andra Marcu

^1,2,

Andreea Serbanica

^1,2,

Ana Bica

^1,2,

Cristina Jercan

^1,2

,

Ana Marcu

^1,2,

Dumitru Jardan

³,

Cerasela Jardan

^1,4,

Onda Calugaru

^1,4,

Mihaela Dragomir

⁴

,

Codruta Popa

^1,5

,

Anca Gheorghe

⁵,

Karina Vihta

^3,6

,

Simona Dima

^1,7 and

Anca Colita

^1,2

¹

Faculty of General Medicine, “Carol Davila” University of Medicine and Pharmacy, 020022 Bucharest, Romania

²

Department of Pediatrics, Fundeni Clinical Institute, 022328 Bucharest, Romania

³

Molecular Biology Laboratory, Medlife Clinic, Calea Grivitei No. 371, 012244 Bucharest, Romania

⁴

Genetics Laboratory, Fundeni Clinical Institute, 022328 Bucharest, Romania

⁵

Flow Cytometry Laboratory, Fundeni Clinical Institute, 022328 Bucharest, Romania

⁶

Biostatistics, Fundeni Clinical Institute, 022328 Bucharest, Romania

⁷

Center of Excellence in Translational Medicine (CEMT), Fundeni Clinical Institute, 022328 Bucharest, Romania

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(10), 4517; https://doi.org/10.3390/ijms27104517

Submission received: 24 April 2026 / Revised: 14 May 2026 / Accepted: 15 May 2026 / Published: 18 May 2026

(This article belongs to the Section Molecular Genetics and Genomics)

Download Versions Notes

Abstract

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and genomic profiling has become increasingly vital for risk stratification. We conducted a retrospective single-center study including 96 newly diagnosed pediatric patients with ALL and mixed phenotype acute leukemia to characterize the genomic landscape using conventional and molecular cytogenetics, multiplex ligation-dependent probe amplification and targeted next-generation sequencing and to evaluate associations with treatment response and survival. Mutation co-occurrence analysis revealed a NRAS/KRAS/JAK cluster and an ETV6::RUNX1 cluster characterized by relative mutational exclusivity, with additional associations between NOTCH1–CDK4 and CDK4–CCND3 alterations. DelCDKN2A/CDKN2B alterations showed a trend toward higher day-15 minimal residual disease (MRD) levels and inferior 2-year event free survival rate (EFS). DelIKZF1-positive cases showed lower 2-year EFS. In contrast, ETV6::RUNX1 and high hyperdiploidy were associated with favorable early response and EFS. DelPAX5 did not independently influence outcome. ZNF384 positive cases showed higher early MRD levels despite excellent survival outcomes. NRAS/KRAS mutations were significantly associated with higher positive day-15 MRD (Wilcoxon, p = 0.0067) and remained independently associated after adjustment for white blood cell count and cytogenetic subgroup. Intermediate risk (IR) and high-risk groups showed comparable 2-year EFS, indicating limited discrimination by conventional risk stratification. The IR group displayed a heterogeneous genomic profile, with NRAS/KRAS, Ph-like mutations and delCDKN2A/CDKN2B among the most frequent alterations. These observations highlight the potential of integrated genomic profiling to refine risk stratification, particularly by identifying clinically relevant subgroups within the IR category.

Keywords: acute lymphoblastic leukemia; next-generation sequencing; RAS pathway mutations

Share and Cite

MDPI and ACS Style

Stefan-Hodorogea, A.; Radu, L.; Marcu, A.; Serbanica, A.; Bica, A.; Jercan, C.; Marcu, A.; Jardan, D.; Jardan, C.; Calugaru, O.; et al. Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response. Int. J. Mol. Sci. 2026, 27, 4517. https://doi.org/10.3390/ijms27104517

AMA Style

Stefan-Hodorogea A, Radu L, Marcu A, Serbanica A, Bica A, Jercan C, Marcu A, Jardan D, Jardan C, Calugaru O, et al. Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response. International Journal of Molecular Sciences. 2026; 27(10):4517. https://doi.org/10.3390/ijms27104517

Chicago/Turabian Style

Stefan-Hodorogea, Andreea, Letitia Radu, Andra Marcu, Andreea Serbanica, Ana Bica, Cristina Jercan, Ana Marcu, Dumitru Jardan, Cerasela Jardan, Onda Calugaru, and et al. 2026. "Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response" International Journal of Molecular Sciences 27, no. 10: 4517. https://doi.org/10.3390/ijms27104517

APA Style

Stefan-Hodorogea, A., Radu, L., Marcu, A., Serbanica, A., Bica, A., Jercan, C., Marcu, A., Jardan, D., Jardan, C., Calugaru, O., Dragomir, M., Popa, C., Gheorghe, A., Vihta, K., Dima, S., & Colita, A. (2026). Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response. International Journal of Molecular Sciences, 27(10), 4517. https://doi.org/10.3390/ijms27104517

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Menu

Integrated Genomic Profiling of Pediatric Acute Lymphoblastic Leukemia: Genomic Landscape, Risk Stratification and Association of RAS Pathway Mutations with Early Treatment Response

Abstract

Share and Cite

Article Metrics

Article Access Statistics

Further Information

Guidelines

MDPI Initiatives

Follow MDPI