Genetic variation of acquired structural chromosomal aberrations

0496009 - ÚEM 2019 RIV NL eng J - Článek v odborném periodiku
Vodička, Pavel - Mušák, L. - Vodičková, Ludmila - Vodenková, Soňa - Catalano, C. - Kroupa, Michal - Naccarati, Alessio - Polívková, Z. - Vymetálková, Veronika - Försti, A. - Hemminki, K.
Genetic variation of acquired structural chromosomal aberrations.
Mutation Research - Genetic Toxicology and Environmental Mutagenesis. Roč. 836, SI (2018), s. 13-21. ISSN 1383-5718. E-ISSN 1879-3592
Grant CEP: GA ČR(CZ) GA15-14789S; GA MZd(CZ) NV15-27580A
Institucionální podpora: RVO:68378041
Klíčová slova: chromosomal aberrations * genetics * xenobiotic metabolizing enzymes
Obor OECD: Epidemiology
Impakt faktor: 2.256, rok: 2018

Genomic instability is considered as a causative event in malignant transformation and may be manifested as genetic changes in the nucleotide sequence of DNA, or as structural or numerical changes of chromosomes. Unrepaired or insufficiently repaired DNA double-strand breaks, as well as telomere shortening, are important contributors in the formation of structural chromosomal aberrations-CA. In the present review, we discuss potential mechanisms behind the formation of CAs and their relation to cancer - how inherited genetic variation may modify the frequency and types of CAs occurring in humans. We published a series of studies on variations in genes relevant to maintaining genomic integrity: those encoding xenobiotic-metabolising enzymes, DNA repair, the tumour suppressor TP53, the spindle assembly checkpoint, and cyclin D1. While individually genetic variation in these genes exerted small modulating effects, in interactions they were associated with CA frequencies in peripheral blood lymphocytes of healthy volunteers. Moreover, we observed opposite associations between the cyclin D1 splice site polymorphism rs9344 G870A and the frequency of CA compared to their association with translocation t(11,14). We discuss the functional consequences of the cyclin D1 gene in interplay with DNA damage response and DNA repair during malignant transformation. Our review summarizes existing evidence that gene variations in relevant cellular pathways modulate the frequency of CA, predominantly in a complex interaction. More functional/mechanistic studies are required. Several questions emerge - the role of CAs in malignancies with respect to a particular phenotype and heterogeneity, the formation of CAs during the process of malignant transformation, and the formation of CA in lymphocytes in relation to the immune response.
Trvalý link: http://hdl.handle.net/11104/0294077