Pavlina Chelenkova

Children of the Sun, Children of the Moon—A Mini-Panel for Assessment of Inter-Individual Variation Between the Capacity of Healthy Individuals to Repair Everyday Genotoxic Insults

ABSTRACT The DNA repair machinery of healthy human cells usually manages the consequences of the daily barrage of DNA damage for years and decades before any adverse effects related to genotoxic impact become manifest. There is significant variance, however, even between healthy individuals, in regard to their ability to detect and repair genotoxic damage. Some aspects of this variance exist throughout the life of the individual (genetic factors, such as polymorphisms in genes coding for products acting in the repair of DNA damage), while others (e.g. telomere length) may be the outcome of the genotype-phenotype interplay, modified by environmental factors. Numerous markers for assessment of capacity to combat genotoxic damage have been described so far, with only some of them having a value of their own under physiological and/or pathological conditions. In the present study we provide the results from the evaluation of a mini-panel (p53 P72R, XPCins83PAT, rate of telomere attrition) for assessing the capacity of healthy individuals to repair genotoxic damage, and outline the possible fields of application.

What's your poison? Impact of individual repair capacity on the outcomes of genotoxic therapies in cancer. Part II - information content and validity of biomarkers for individual repair capacity in the assessment of outcomes of anticancer therapy.

ABSTRACT The individual variance in the efficiency of repair of damage induced by genotoxic therapies may be an important factor in the assessment of eligibility for different anticancer treatments, the outcomes of various treatments and the therapy-associated complications, including acute and delayed toxicity and acquired drug resistance. The second part of this paper analyses the currently available information about the possibilities of using experimentally obtained knowledge about individual repair capacity for the purposes of personalised medicine and healthcare.

WHAT'S YOUR POISON? IMPACT OF INDIVIDUAL REPAIR CAPACITY ON THE OUTCOMES OF GENOTOXIC THERAPIES IN CANCER. PART I - ROLE OF INDIVIDUAL REPAIR CAPACITY IN THE CONSTITUTION OF RISK FOR LATE-ONSET MULTIFACTORIAL DISEASE

ABSTRACT The capacity for repair of damage in DNA may vary between clinically healthy people and in patients with different diseases and conditions, contributing to the risk for development of late-onset multifactorial disease, eligibility for different therapies and various therapy-related complications. At present, the effects of individual variance in DNA repair capacity in human disease are best studied in cancer. The first part of this paper briefly reviews the history of the field and the currently available biomarkers of individual repair capacity associated with the risk for development of cancer and other late-onset multifactorial diseases and conditions.

Brown Trout-Salmon Hybrids in Bulgarian Rivers are not a Red Herring

ABSTRACT Brown trout (Salmo trutta fario) is a popular object of recreational fishing in Bulgaria and throughout Europe. Free-living (‘wild’) populations of brown trout are seen in many cold water rivers, and restocking of artificial as well natural water basins is carried out routinely. Genetic analysis for a microsatellite marker common for several salmonid species but discriminative in regards to species affiliation shows that allele lengths uncharacteristic of brown trout but typical of Atlantic salmon may be observed in Bulgarian ‘wild’ populations of brown trout. It is possible that a subpopulation containing interspecies hybrids with Atlantic salmon exists in the Bulgarian water basins populated with brown trout. Since brown trout-salmon hybrids have been shown to be viable and fertile, the possibility for future interspecies introgression cannot be ruled out. The biodiversity of Bulgarian natural populations of salmonid fishes may benefit from a more finely tailored stocking strategy.

HPV Has Left the Building—the Absence of Detectable HPV DNA and the Presence of R Allele/S for the P72R Polymorphism in the TP53 Gene May Call for More Aggressive Therapeutic Approach in HPV-Associated Tumours

ABSTRACT HPV infection is a major pathogenetic factor in cervical carcinoma as well as in many of the squamous cancers of head and neck and other epithelial cancers. Persistence of HPV DNA detectable by routine methods is considered to be a risk factor for advanced CIN and, in patients treated by surgery or non-surgical treatment modalities (radiotherapy, chemotherapy), HPV persistence is believed to be associated with increased risk for local recurrence. In terms of survival, however, it has been repeatedly proven that patients with cervical cancer and other HPV-associated cancers with detectable HPV DNA tend to have better outcomes than patients with HPV-negative tumours. The P72R polymorphism in the human TP53 gene has been contemplated as an independent phenotype modifier in cancers, especially the R allele which has been shown to confer higher pro-apoptotic properties to the resultant p53 protein. It has been demonstrated, however, that RR homozygotes were much more common in study groups with HPV-associated tumours than the other two genotypes and that the P allele in P/R heterozygotes was preferentially lost while the R allele was preferentially retained and mutated. It is possible that HPV-dependent carcinogenesis strictly relies on the presence of HPV and the expression of the E6 and E7 oncoproteins only in the initial phases of transformation of infected cells (e.g. CIN). It may be associated with activation of latent HPV that would create a background of decreased control over the integrity of the genome of the host cell. The process can develop further by mechanisms independent of the presence of HPV and if the virus clears at some later point, that would not halt the already ongoing neoplastic transformation. Absence of HPV DNA in cervical tumours, whether before or after treatment, is not a reason to decrease vigilant monitoring and rule out the need for further treatment, as it may be quite possible that the TP53 gene of the infected cells has already been modified in the course of cancer progression by HPV-independent mutagenesis. Cervical tumours that are HPV-negative ought to alert attending oncologists for the possibility for increased growth potential and invasiveness of the tumour so as to contemplate more aggressive anticancer therapies, especially in carriers of the R allele of the P53R polymorphism.

One Fish, Two Fish, Old Fish, New Fish—Is the Biodiversity of Bulgarian Native Brown Trout (S. Trutta Fario) Populations at Risk?

ABSTRACT Human impact on genetic variability of species is a prominent cause for loss of biodiversity on a global scale. The present work offers evidence that the genetic diversity in Bulgarian native populations of brown trout is already failing because of alteration of the population structure via enhanced human-mediated assortative mating and/or interspecies hybridisation with other salmonids. The risk of adverse genetic consequences to the native populations is already significant. Bulgarian aquaculture may benefit from more strict control policy over stock transfer and release offish and stock material into the natural water basins.

Frequency of the common promoter polymorphism MMP2 -1306 C>T in a population from central Bulgaria.

Matrix metalloproteinases (MMPs) are a family of highly homologous extracellular Zn2+-dependent endopeptidases, also known as matrixins. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) are considered to play a key role in a variety of physiological processes as well as in the development and progression of a vast majority of pathological conditions. Most of the genes encoding MMPs, including MMP-2, are highly polymorphic. One of the single nucleotide polymorphisms with functional activity in the promoter region of MMP2 is the transition MMP2 −1306C>T (rs243865). The aim of the present study was to evaluate the genotype and allele frequencies of the common promoter polymorphism −1306C>T in MMP2 in 75 individuals from central Bulgaria and to compare our results with those of other population studies. We found that 76.0% of the randomly enrolled individuals are carriers of the CC genotype, 17.3% of CT, and 6.7% of the TT genotype. The minor allele frequency (MAF) was 15.3%. Interestingly, the obtained genotype frequencies appeared to differ from those of some other Caucasian populations (USA – 55/38/7, MAF 26%; The Netherlands – 52.8/40.5/6.7, MAF 26.9%; Austria – 55.6/35.5/8.9, MAF 27.2%), but were closer to the values of the reported global genotype distribution (75.3/21.3/3.4, MAF 14%).