Chromosomal Damage As Markers Of Genotoxicity And Carcinogenesis

Human cancers arise from cells unable to maintain genomic and chromosomal stability, mainly as a sequential consequence of altered DNA repair mechanisms (base and nucleotide excision, mismatch and double-strand breaks). Chromosomal aberrations (CAs) are a marker of cancer risk and many specific CAs represent causative events in malignant transformation. Non-specific CAs arise as a result of direct DNA damage by ionizing radiation (chromosome-breaks; CSA) or replication on a damaged DNA template (CSA and chromatide-breaks; CTA). Frequencies of CAs in blood lymphocytes (PBL) are predictive for cancer risk in prospective epidemiological studies and patients with many types of cancer show elevated CAs at diagnosis. We have recently disclosed associations of CAs with variants in genes encoding DNA repair and xenobiotic metabolizing enzymes on 1800 healthy subjects exposed and unexposed to potentially carcinogenic compounds. Notably, lower frequencies of CAs and CTA are associated with high activity EPHX1 and XPD Lys751Gln homozygous variant genotypes and several pair-wise interactions significantly modulated CA, CTA and CSA frequencies. On the contrary, increased CAs and CSA frequencies were observed in subjects bearing splicing A variant in CCND1 G870A. Current investigations aim at understanding the genetics underlying CAs as intermediary cancer biomarkers, such as variants in genes encoding kinetochores, mitotic apparatus regulating enzymes, variants in genes encoding polymerases in DNA repair synthesis and the CAs dynamics in subjects repeatedly analysed over time. We have also explored miRNA binding sites in 3′UTR of DNA repair genes (BER, NER and DSB) both in colorectal cancer patients and in healthy subjects with CAs. Since shortening of telomeres in each cell division may lead to telomere crisis and complex CAs, relative telomere length (RTL) was determined in 187 individuals and compared to their CA count in PBL. Further analyses investigated RTL in incident cancer patients (breast, colorectum and lungs) and in patients (breast and colorectum) with the estimated double-strand breaks repair capacity. CAs detected in patients with above solid cancers were associated with clinicopathological characteristics and analysed as a potential prognostic factors. Our studies suggest that CAs in PBL may represent perspective transient marker in carcinogenesis and we hereby provide a biological basis for the link between CAs and cancer risk along with the genetic control of the overall CA frequency. Grant support: GA CR 15-14789S, AZV 15-27580A and COST LD14050. Citation Format: Pavel E. Vodicka, Ludmila Vodickova, Zdena Polivkova, Ludovit Musak, Maria Dusinska, Sona Vodenkova, Veronika Vymetalkova, Michal Kroupa, Alessio Naccarati, Rajiv Kumar, Kari J. Hemminki. Chromosomal damage as markers of genotoxicity and carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 801.