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

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: We found a strong correlation between tumor mutational burden (TMB) and neoantigen load (<i>p</i> < 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 (<i>p</i> < 0.001). Also, differences between B- and T-cell ALL were found but statistical significance did not remain after permutation. <b>Conclusions</b>: 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.

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Journal
Pharmaceuticals
Published
2025-09-18
DOI
https://doi.org/10.3390/ph18091405
Primary Topic
Lymphoma Diagnosis and Treatment
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article
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article

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

Haydeé Rosas‐Vargas, Laura Elizabeth Merino‐Pasaye, Raquel Amador‐Sánchez, Janet Flores‐Lujano et al.
Pharmaceuticals
Lymphoma Diagnosis and Treatment
article

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

Haydeé Rosas‐Vargas, Laura Elizabeth Merino‐Pasaye, Raquel Amador‐Sánchez, Janet Flores‐Lujano, José Refugio Torres‐Nava, Juan Carlos Núñez-Enríquez, Silvia Jiménez‐Morales, Martha Margarita Velázquez‐Aviña, Rosa Martha Espinosa‐Elizondo, Diana Karen Mendiola-Soto, Didier Ismael May-Hau, Elva Jiménez‐Hernández, Maria Luisa Pérez‐Saldívar, José Gabriel Peñaloza‐González, Luz Victoria Flores‐Villegas, Aurora Medina‐Sansón, Vilma Carolina Bekker‐Méndez, Laura Gómez-Romero, Carlos Jhovani Pérez-Amado, Jorge Alfonso Martín‐Trejo, Minerva Mata‐Rocha, Karina Anastacia Solís‐Labastida, Omar Alejandro Sepúlveda‐Robles, David Aldebarán Duarte-Rodríguez, Juan Manuel Mejía‐Aranguré
article en

Abstract

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: We found a strong correlation between tumor mutational burden (TMB) and neoantigen load (<i>p</i> < 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 (<i>p</i> < 0.001). Also, differences between B- and T-cell ALL were found but statistical significance did not remain after permutation. <b>Conclusions</b>: 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.

PharmaceuticalsVol. 18(9)
Mexican Social Security Institute (MX), Universidad Autónoma de la Ciudad de México (MX), Hospital General de México (MX), Centro Médico Nacional La Raza (MX), Secretaria de Salud (MX), Hospital Infantil de México Federico Gómez (MX), National Institute of Genomic Medicine (MX), Secretaria de Salud (HN), Centro Medico Nacional Siglo XXI (MX), Hospital General De Zona (MX), Hospital de Especialidades (MX), Hospital Pediátrico Moctezuma (MX), Instituto de Medicina Genómica (ES), Hospital Juárez de México (MX), Institute for Social Security and Services for State Workers (MX), Universidad Nacional Autónoma de México (MX), Tecnológico de Monterrey (MX)
Openalex Percentile: Top 64%
Lymphoma Diagnosis and Treatment
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