Hypoxia increases mutational load of breast cancer cells through frameshift mutations

Goutham Hassan Venkatesh, Pamela Bravo, Walid Shaaban Moustafa Elsayed, Francis Amirtharaj, Bartosz Wojtas, Raefa Abou Khouzam, Husam Hussein Nawafleh, Sandeep Mallya, Kapaettu Satyamoorthy, Philippe Dessen, Filippo Rosselli, Jerome Thiery, Salem Chouaib

Research output: Contribution to journalArticle

Abstract

Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and non-recurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.

Original languageEnglish
Article number1750750
JournalOncoImmunology
Volume9
Issue number1
DOIs
Publication statusPublished - 01-01-2020

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology

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  • Cite this

    Hassan Venkatesh, G., Bravo, P., Shaaban Moustafa Elsayed, W., Amirtharaj, F., Wojtas, B., Abou Khouzam, R., Hussein Nawafleh, H., Mallya, S., Satyamoorthy, K., Dessen, P., Rosselli, F., Thiery, J., & Chouaib, S. (2020). Hypoxia increases mutational load of breast cancer cells through frameshift mutations. OncoImmunology, 9(1), [1750750]. https://doi.org/10.1080/2162402X.2020.1750750