Polymorphisms in MDM2 and TP53 Genes and Risk of Developing Therapy-Related Myeloid Neoplasms

Maria Cabezas, Lydia García-Quevedo, Cintia Alonso, Marta Manubens, Yolanda Álvarez, Joan Francesc Barquinero, Santiago Ramón y Cajal, Margarita Ortega, Adoración Blanco, María Rosa Caballín, Gemma Armengol

Research output: Contribution to journalArticleResearch

2 Citations (Scopus)

Abstract

© 2019, The Author(s). One of the most severe complications after successful cancer therapy is the development of therapy-related myeloid neoplasms (t-MN). Constitutional genetic variation is likely to impact on t-MN risk. We aimed to evaluate if polymorphisms in the p53 pathway can be useful for predicting t-MN susceptibility. First, an association study revealed that the Pro variant of the TP53 Arg72Pro polymorphism and the G allele of the MDM2 SNP309 were associated with t-MN risk. The Arg variant of TP53 is more efficient at inducing apoptosis, whereas the Pro variant is a more potent inductor of cell cycle arrest and DNA repair. As regards MDM2 SNP309, the G allele is associated with attenuation of the p53 apoptotic response. Second, to evaluate the biological effect of the TP53 polymorphism, we established Jurkat isogenic cell lines expressing p53Arg or p53Pro. Jurkat p53Arg cells presented higher DNA damage and higher apoptotic potential than p53Pro cells, after treatment with chemotherapy agents. Only p53Pro cells presented t(15;17) translocation and del(5q). We suggest that failure to repair DNA lesions in p53Arg cells would lead them to apoptosis, whereas some p53Pro cells, prone to cell cycle arrest and DNA repair, could undergo misrepair, generating chromosomal abnormalities typical of t-MN.
Original languageEnglish
Article number150
Pages (from-to)150
Number of pages10
JournalScientific Reports
Volume9
Issue number150
DOIs
Publication statusPublished - 17 Jan 2019

Keywords

  • ASSOCIATION
  • CANCER
  • DNA-REPAIR CAPACITY
  • DOUBLE-STRAND BREAKS
  • LEUKEMIA
  • P53
  • PATHWAY
  • SINGLE NUCLEOTIDE POLYMORPHISM
  • TRANSCRIPTION
  • VARIANTS

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