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

Autor:	Gemma Armengol, Santiago Ramón y Cajal, María Rosa Caballín, Joan Francesc Barquinero, L. Garcia-Quevedo, Cintia Alonso, Margarita Ortega, Adoración Blanco, Yolanda Álvarez, Marta Manubens, Maria Cabezas
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Male Myeloid Cell cycle checkpoint DNA repair DNA damage lcsh:Medicine Biology Jurkat cells Polymorphism Single Nucleotide Article 03 medical and health sciences Jurkat Cells 0302 clinical medicine Risk Factors medicine Leukaemia Humans Genetic Predisposition to Disease Allele lcsh:Science Cancer genetics Multidisciplinary Leukemia DNA damage and repair lcsh:R Neoplasms Second Primary Proto-Oncogene Proteins c-mdm2 Isogenic human disease models Mechanisms of disease 030104 developmental biology medicine.anatomical_structure Apoptosis Cancer research Female lcsh:Q Tumor Suppressor Protein p53 030217 neurology & neurosurgery
Zdroj:	Scientific Reports, Vol 9, Iss 1, Pp 1-10 (2019) Scientific Reports Dipòsit Digital de Documents de la UAB Universitat Autònoma de Barcelona
ISSN:	2045-2322
DOI:	10.1038/s41598-018-36931-x
Popis:	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.
Databáze:	OpenAIRE
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