APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer

Irina Bobrovnitchaia, Renan Valieris, Rodrigo D. Drummond, Joao P. Lima, Helano C. Freitas, Thais F. Bartelli, Maria G. de Amorim, Diana N. Nunes, Emmanuel Dias-Neto, Israel T. da Silva

Research output: Contribution to journalArticle

Abstract

Mechanisms of viral oncogenesis are diverse and include the off-target activity of enzymes expressed by the infected cells, which evolved to target viral genomes for controlling their infection. Among these enzymes, the single-strand DNA editing capability of APOBECs represent a well-conserved viral infection response that can also cause untoward mutations in the host DNA. Here we show, after evaluating somatic single-nucleotide variations and transcriptome data in 240 gastric cancer samples, a positive correlation between APOBEC3s mRNA-expression and the APOBEC-mutation signature, both increased in EBV+ tumors. The correlation was reinforced by the observation of APOBEC mutations preferentially occurring in the genomic loci of the most active transcripts. This EBV infection and APOBEC3 mutation-signature axis were confirmed in a validation cohort of 112 gastric cancer patients. Our findings suggest that APOBEC3 upregulation in EBV+ cancer may boost the mutation load, providing further clues to the mechanisms of EBV-induced gastric carcinogenesis. After further validation, this EBV-APOBEC axis may prove to be a secondary driving force in the mutational evolution of EBV+ gastric tumors, whose consequences in terms of prognosis and treatment implications should be vetted.

Original languageEnglish (US)
Pages (from-to)181-191
Number of pages11
JournalInternational Journal of Cancer
Volume146
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Human Herpesvirus 4
Stomach Neoplasms
Carcinogenesis
Mutation
DNA
Stomach
Neoplasms
Epstein-Barr Virus Infections
Viral Genome
Virus Diseases
Enzymes
Transcriptome
Up-Regulation
Nucleotides
Observation
Messenger RNA
Infection
Therapeutics

Keywords

  • APOBEC
  • EBV
  • gastric cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bobrovnitchaia, I., Valieris, R., Drummond, R. D., Lima, J. P., Freitas, H. C., Bartelli, T. F., ... da Silva, I. T. (2020). APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer. International Journal of Cancer, 146(1), 181-191. https://doi.org/10.1002/ijc.32411

APOBEC-mediated DNA alterations : A possible new mechanism of carcinogenesis in EBV-positive gastric cancer. / Bobrovnitchaia, Irina; Valieris, Renan; Drummond, Rodrigo D.; Lima, Joao P.; Freitas, Helano C.; Bartelli, Thais F.; de Amorim, Maria G.; Nunes, Diana N.; Dias-Neto, Emmanuel; da Silva, Israel T.

In: International Journal of Cancer, Vol. 146, No. 1, 01.01.2020, p. 181-191.

Research output: Contribution to journalArticle

Bobrovnitchaia, I, Valieris, R, Drummond, RD, Lima, JP, Freitas, HC, Bartelli, TF, de Amorim, MG, Nunes, DN, Dias-Neto, E & da Silva, IT 2020, 'APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer', International Journal of Cancer, vol. 146, no. 1, pp. 181-191. https://doi.org/10.1002/ijc.32411
Bobrovnitchaia I, Valieris R, Drummond RD, Lima JP, Freitas HC, Bartelli TF et al. APOBEC-mediated DNA alterations: A possible new mechanism of carcinogenesis in EBV-positive gastric cancer. International Journal of Cancer. 2020 Jan 1;146(1):181-191. https://doi.org/10.1002/ijc.32411
Bobrovnitchaia, Irina ; Valieris, Renan ; Drummond, Rodrigo D. ; Lima, Joao P. ; Freitas, Helano C. ; Bartelli, Thais F. ; de Amorim, Maria G. ; Nunes, Diana N. ; Dias-Neto, Emmanuel ; da Silva, Israel T. / APOBEC-mediated DNA alterations : A possible new mechanism of carcinogenesis in EBV-positive gastric cancer. In: International Journal of Cancer. 2020 ; Vol. 146, No. 1. pp. 181-191.
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