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Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker

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Abstract

Purpose

Astrocytomas are a type of malignant brain tumor with an unfavorable clinical course. The impact of AGT and MGMT somatic variants in the prognosis of astrocytoma is unknown, and it is controversial for TP53. Moreover, there is a lack of knowledge regarding the molecular characteristics of astrocytomas in Mexican patients.

Methods

We studied 48 Mexican patients, men and women, with astrocytoma (discovery cohort). We performed DNA deep sequencing in tumor samples, targeting AGT, MGMT and TP53, and we studied MGMT gene promoter methylation status. Then we compared our findings to a cohort which included data from patients with astrocytoma from The Cancer Genome Atlas (validation cohort).

Results

In the discovery cohort, we found a higher number of somatic variants in AGT and MGMT than in the validation cohort (10.4% vs < 1%, p < 0.001), and, in both cohorts, we observed only women carried variants AGT variants. We also found that the presence of either MGMT variant or promoter methylation was associated to better survival and response to chemotherapy, and, in conjunction with TP53 variants, to progression-free survival.

Conclusions

The occurrence of AGT variants only in women expands our knowledge about the molecular differences in astrocytoma between men and women. The increased prevalence of AGT and MGMT variants in the discovery cohort also points towards possible distinctions in the molecular landscape of astrocytoma among populations. Our findings warrant further study.

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Data availability

DNA sequences from the discovery cohort were deposited at NCBI’s Sequence Read Archive (Bioproject PRJNA862290). TCGA data was obtained from https://xenabrowser.net/datapages/, TCGA Glioblastoma and TCGA Lower Grade Glioma.

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Acknowledgements

We sincerely thank Laura Márquez, Patricia de la Torre and Patricia Rosas for their contributions in the project. Many thanks to the PECEM and the Universidad Nacional Autónoma de México (UNAM) for their support of this project.

Funding

This research was funded by the Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico: Salud 2013-01-202720 to TWO. Scolarship number 969754 to JACE).

Author information

Authors and Affiliations

  1. PECEM (MD/PhD), Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    José Alberto Carlos-Escalante

  2. Departamento de Enseñanza, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, 14269, Mexico City, Mexico

    Sonia Iliana Mejía-Pérez

  3. Departamento de Ciencias Naturales, Universidad Autónoma Metropolitana-Cuajimalpa, 05370, Mexico City, Mexico

    Ernesto Soto-Reyes & Lissania Guerra-Calderas

  4. Unidad de Neuro-Oncología, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico

    Bernardo Cacho-Díaz

  5. Unidad de Investigación Biomédica en Cáncer, Instituto Nacional de Cancerología-Instituto de Investigaciones Biomédicas, UNAM, 14080, Mexico City, Mexico

    Karla Torres-Arciga, Michel Montalvo-Casimiro, Rodrigo González-Barrios & Cristian Arriaga-Canon

  6. Dirección de Investigación, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico

    Nancy Reynoso-Noverón

  7. Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico

    Miguel Ruiz-de la Cruz, Clara Estela Díaz-Velásquez & Felipe Vaca-Paniagua

  8. Departamento de Infectómica y Patogénsis Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), 07360, Mexico City, Mexico

    Miguel Ruiz-de la Cruz

  9. Clínica de Cáncer Hereditario, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico

    Silvia Vidal-Millán & Rosa María Álvarez-Gómez

  10. Departamento de Neurocirugía, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suarez”, 14269, Mexico City, Mexico

    Thalía Estefanía Sánchez-Correa & Claudio Hiram Pech-Cervantes

  11. Departamento de Traumatología y Ortopedia, Hospital General Regional #2, Instituto Mexicano del Seguro Social, 14310, Mexico City, Mexico

    José Antonio Soria-Lucio

  12. Departamento de Cirugía, Hospital General Regional #1, Instituto Mexicano del Seguro Social, 61303, Charo, Mexico

    Areli Pérez-Castillo

  13. Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Ana María Salazar, Aliesha González-Arenas & Patricia Ostrosky-Wegman

  14. Subdirección de Investigación Básica, Instituto Nacional de Cancerología, 14080, Mexico City, Mexico

    Felipe Vaca-Paniagua & Talia Wegman-Ostrosky

  15. Laboratorio Nacional en Salud: Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-Degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, 54090, Tlalnepantla, Mexico

    Clara Estela Díaz-Velásquez & Felipe Vaca-Paniagua

  16. Unidad de Epidemiología e Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, UNAM-INCAN, 14080, Mexico City, Mexico

    Alejandro Mohar-Betancourt

  17. Dirección General, Instituto Nacional de Medicina Genómica (INMEGEN), 14610, Mexico City, Mexico

    Luis A. Herrera

  18. Laboratorio Clínico de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía, “Manuel Velasco Suárez”, 14269, Mexico City, Mexico

    Teresa Corona

  19. División de Estudios de Posgrado, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, Mexico City, Mexico

    Teresa Corona

Authors
  1. José Alberto Carlos-Escalante
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  2. Sonia Iliana Mejía-Pérez
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  3. Ernesto Soto-Reyes
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  4. Lissania Guerra-Calderas
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  5. Bernardo Cacho-Díaz
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  6. Karla Torres-Arciga
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  7. Michel Montalvo-Casimiro
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  8. Rodrigo González-Barrios
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  9. Nancy Reynoso-Noverón
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  10. Miguel Ruiz-de la Cruz
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  11. Clara Estela Díaz-Velásquez
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  14. Thalía Estefanía Sánchez-Correa
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  15. Claudio Hiram Pech-Cervantes
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  16. José Antonio Soria-Lucio
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  17. Areli Pérez-Castillo
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  18. Ana María Salazar
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  19. Cristian Arriaga-Canon
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  20. Felipe Vaca-Paniagua
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  21. Aliesha González-Arenas
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  22. Patricia Ostrosky-Wegman
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  23. Alejandro Mohar-Betancourt
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  24. Luis A. Herrera
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  25. Teresa Corona
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  26. Talia Wegman-Ostrosky
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Contributions

Conceptualization: TWO, SVM, TC, POW, SIMP, and BCD. Data Curation: JACE, SI MP, TWO. Formal Analysis: JACE. Funding Acquisition: TWO, AMB, and LAH. Investigation: ESR, TWO, LGC, SIMP, JACE, KTA, MMC, RMAG, AMSM, APC, JASL, CHPC, TESC, MRC, and CEDV. Methodology: JACE, SIMP and TWO. Resources: TWO, CEDV, RGB, CAC, FVP, POW. Supervision: TWO, CAC and FVP. Validation: JACE, NRN, MRC, and CEDV. Visualization: JSCE. Writing – Original Draft: JA CE, AGA, and TWO. Writing – Review & Editing: All Authors.

Corresponding author

Correspondence to Talia Wegman-Ostrosky.

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Written informed consent was obtained from all individuals participating in the study.

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The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Institutional Board Review of the Instituto National de Neurología y Neurocirugía, registry number 67/12.

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Carlos-Escalante, J.A., Mejía-Pérez, S.I., Soto-Reyes, E. et al. Deep DNA sequencing of MGMT, TP53 and AGT in Mexican astrocytoma patients identifies an excess of genetic variants in women and a predictive biomarker. J Neurooncol 161, 165–174 (2023). https://doi.org/10.1007/s11060-022-04214-1

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