Background: Adaptive response to hypoxia is regulated by several mechanisms and transcription factors, includ ing hypoxia-inducible factors (HIFs). Activation of HIF-1α is associated with increased expression of P-glycoprotein and multidrug resistance in cancer cells. In this retrospective study, we analyzed candidate single-nucleotide polymorphisms (SNPs) in HIF-1α and HIF-1β associated with risk of monoclonal gammopathy of undetermined significance (MGUS) or multiple myeloma (MM). Patients and Methods: Genotypes of SNPs associated with hypoxia were determined in an independent cohort of monoclonal gammopathies (MG) (275 MM and 228 MGUS patients) and in 219 cancer-free controls by real time polymerase chain reaction allelic discrimination. Results: When MM patients were compared to controls, protective role of CG genotype compared to CC in HIF-1β (rs2228099) for MM development was observed (OR = 0.65; CI 0.45-0.95; p = 0.026). Even after adjustment for patients' age and body mass index (BMI), there were significantly lower odds (OR = 0.55; p = 0.045) of develop ing MM patients of CG genotype in comparison to CC genotype. Log-rank test confirmed association of GT haplotype (rs11549467, rs2057482) in HIF-1α with better over all survival (median 41.8 months; (CI 35.1-48.5)) for "none GT" and median 93.8 months (CI 31.3-156.4) for "at least one GT" haplotype (p = 0.0500). Further, significant associations between SNPs in MDR1 and outcome of MM were found in 110 MM patients that underwent bortezomib-based treatment. Conclusion: Our study showed a genetic predisposition for risk of MG development and/ or outcome of MM patients; nevertheless, further studies are needed to confirm our initial analysis.
Volná cirkulující DNA (cf-DNA) je charakterizována jako extracelulární DNA, která může být přítomna v nízkých koncentracích v krvi zdravých jedinců. Cf-DNA je do krevního řečiště uvolňována apoptózou, ale i nekrózou. Zvýšené hladiny se vyskytují u patologických stavů, jako je zánět, stres či autoimunitní onemocnění. Výrazně zvýšené hodnoty cf-DNA jsou patrné zejména u pacientů s malignitami, a to především v pokročilých stadiích nemoci. V takovémto případě je nádorově specifi cká cf-DNA uvolňována nekrózou z buněk primárního nádoru a metastáz. V poslední době se hodně studií zabývá tzv. liquid bio psy (tekutou bio psií), která umožňuje poměrně snadnou detekci cirkulujících nádorových buněk i cirkulujících molekul nukleových kyselin z periferní krve k diagnostice nádorových onemocnění. Kvantitativní stanovení a detekce genetických a epigenetických změn v cf-DNA u pacientů s různými malignitami má potenciální využití v molekulární diagnostice, prognóze, monitorování průběhu nemoci a odpovědi na léčbu. Tento článek je zaměřen na potenciální využití cf-DNA jako krevního biomarkeru u vybraných solidních nádorů a hematologických malignit. Klíčová slovavolná cirkulující DNA -nádorový marker -solidní nádory -hematologické malignity SummaryCirculating cell-free DNA (cf-DNA) is characterized as extracellular DNA that may be present in the blood of healthy individuals in low concentrations. Cf-DNA is released by apoptosis or necrosis into the bloodstream. Increased levels are found in pathological conditions, such as infl ammation, autoimmune diseases, or stress. Signifi cant increase of cf-DNA is particularly evident in patients with malignancies, especially in the advanced stages of the disease. In this case, the tumor specifi c cf-DNA is released by necrosis from the cells of primary tumor and metastases. Recently, many studies concentrate on the so-called 'liquid bio psies' that allow detection of circulating tumor cells and circulating nucleic acids from peripheral blood for tumor diagnostics. Quantitative methods and detection of genetic and epigenetic alternations of cf-DNA in patients with diff erent malignancies have potential applications in molecular diagnosis, prognosis, monitoring of disease progression and response to treatment. This review focuses on potential utility of cf-DNA as a blood bio marker in selected solid tumors and hematologic malignancies.
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