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. 2025 Sep 18;18(9):1405.
doi: 10.3390/ph18091405.

Somatic Mutations in DNA Mismatch Repair Genes, Mutation Rate and Neoantigen Load in Acute Lymphoblastic Leukemia

Diana Karen Mendiola-Soto  1   2 , Laura Gómez-Romero  3   4 , Juan Carlos Núñez-Enríquez  5 , Janet Flores-Lujano  6 , Elva Jiménez-Hernández  7 , Aurora Medina-Sansón  8 , Vilma Carolina Bekker-Méndez  9 , Minerva Mata-Rocha  10 , María Luisa Pérez-Saldívar  6 , David Aldebarán Duarte-Rodríguez  11 , José Refugio Torres-Nava  7 , José Gabriel Peñaloza-González  12 , Luz Victoria Flores-Villegas  13 , Raquel Amador-Sánchez  14 , Martha Margarita Velázquez-Aviña  12 , Jorge Alfonso Martín-Trejo  15 , Laura Elizabeth Merino-Pasaye  16 , Karina Anastacia Solís-Labastida  15 , Rosa Martha Espinosa-Elizondo  17 , Carlos Jhovani Pérez-Amado  1 , Didier Ismael May-Hau  1 , Omar Alejandro Sepúlveda-Robles  18 , Haydee Rosas-Vargas  18 , Juan Manuel Mejía-Aranguré  19   20 , Silvia Jiménez-Morales  1
Affiliations

Somatic Mutations in DNA Mismatch Repair Genes, Mutation Rate and Neoantigen Load in Acute Lymphoblastic Leukemia

Diana Karen Mendiola-Soto et al. Pharmaceuticals (Basel). .

Abstract

Background/Objectives: During cancer development, tumor cells accumulate somatic mutations, which could generate tumor-specific neoantigens. The aberrant protein can be recognized by the immune system as no-self, triggering an immune response against cells expressing this aberrant protein which could mediate tumor control or rejection. Since the expression of this mutated protein is exclusive to tumor cells, great efforts are being made to identify neoantigens of relevance in the development of new cancer treatment strategies. In comparison to adulthood tumors, pediatric malignancies present fewer mutations and thus fewer potential neoantigens. Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy worldwide that can be benefited by the identification of neoantigens for immunotherapy approaches, the landscape of neoantigens in ALL is not well known, therefore the aim of our study was to identify potential neoantigens in ALL pediatric patients. Methods: To identify neoantigens in ALL, whole-exome sequencing of matched tumor-normal cells from pediatric cases was performed, with these data HLA-I alleles predicted and somatic mutations identified to propose potential neoantigens based on binding affinity of mutated peptide-HLA-I. Results: We found a strong correlation between tumor mutational burden (TMB) and neoantigen load (p < 0.001) but no correlation with prognosis. Furthermore, TMB and neoantigens were greater in ALL patients with at least one mutated DNA mismatch repair gene (p < 0.001). Also, differences between B- and T-cell ALL were found but statistical significance did not remain after permutation. Conclusions: The presence of neoantigens in pediatric cases with ALL makes the neoantigen-based immunotherapy a promising new strategy for the treatment of this malignancy, especially for patients with relapse.

Keywords: HLA-A*02:01; HLA-B*39:05; HLA-C*07:01; acute lymphoblastic leukemia; exome sequencing; neoantigens.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Frequency of HLA alleles in pediatric patients with acute lymphoblastic leukemia. HLA–A* (a), HLA–B* (b) and HLA–C* (c) alleles.
Figure 2
Figure 2
Correlation of mutation burden and the number of potential neoantigens.
Figure 3
Figure 3
Mutational burden (a) and tumor neoantigen load (b) in patients carrying missense mutations in DNA mismatch repair genes.
See this image and copyright information in PMC

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