ABSTRACT
PURPOSE: Since the development of the International Germ Cell Cancer Collaborative Group (IGCCCG) risk classification in a 1997 study, high-income countries have reported a significant increase in survival for poor prognosis patients. There are scant data on IGCCCG risk-stratified survival from low- and middle-income countries. We assessed the progression-free survival (PFS) and overall survival (OS) rates in a contemporary cohort of Belarusian patients with advanced germ cell cancer (GCC) stratified by the IGCCCG prognostic classification and analyzed prognostic factors for survival. MATERIALS AND METHODS: The consecutive cohort of patients with clinical stage IIb-III testicular GCC or extragonadal germ cell tumors who received treatment or consultation in our two centers between 2010 and 2015 was included. All patients underwent primary chemotherapy. The patients were divided into seminoma and nonseminomatous germ cell carcinoma (NSGCC) subgroups. The Kaplan-Meier method was used to estimate 5-year PFS and OS. RESULTS: This study included 111 patients with a median age of 32 years, 95% of whom were diagnosed with testicular cancer. Seminoma and NSGCC were identified in 32 (29%) and 79 (71%) patients, respectively. The median follow-up was 6.1 years. The 5-year PFS and OS rates for the entire cohort were 70% and 77%, respectively. In patients with good prognosis seminoma and good, intermediate, and poor prognosis NSGCC, the estimated PFS rates were 76%, 88%, 74%, and 39% and those for OS were 83%, 97%, 83%, and 38%, respectively. CONCLUSION: In our cohort of Belarusian patients with advanced germ cell tumors, we failed to demonstrate an improvement in PFS and OS compared with the 1997 IGCCCG study. Moreover, survival in poor prognosis group is inferior to that in IGCCCG and all contemporary series from high-income countries.
Subject(s)
Neoplasms, Germ Cell and Embryonal , Seminoma , Testicular Neoplasms , Adult , Humans , Male , Neoplasms, Germ Cell and Embryonal/therapy , Prognosis , Republic of Belarus/epidemiologyABSTRACT
BACKGROUND: DNA helicases maintain genome stability, and their deficiency is associated with disorders resembling premature aging as well as contributes to carcinogenesis. Their functions are determined by the respective genes encoding nucleotide excision repair initiating proteins, e.g. XPD and CSB. OBJECTIVE: The present study aimed to investigate the influence of genetic variations in ERCC2/XPD (rs1799793, rs13181) and ERCC6/CSB (rs2228526, rs2228528) loci on lifespan and developing age-related bladder cancer focusing on homozygous wild type alleles. METHOD: The allelic variants were identified in 354 clinically healthy controls and 418 bladder cancer patients using the PCR-RFLP method. RESULTS: The age-depended increase in frequencies of homozygous carriers of wild-type XPD 312Asp and XPD 751Lys alleles was observed among controls, especially among subjects over 80 years (r = 0.67, p = 0.012). The statistically significant correlation was also found between the frequency of homozygous wild type alleles at all tested loci and age in healthy population over 60 years (r = 0.35, p = 0.046) suggesting the relationship between lifespan and longevity, on one hand, and normal functioning of these genes and their products, on the other hand. Homozygous carriers of wild type alleles were less susceptible to bladder cancer, tumor invasion, increase in grade of malignancy and recurrence, but their effects were specific with respect to clinicopathological and lifestyle characteristics. CONCLUSION: Homozygous wild type alleles encoding XPD and CSB proteins with optimal properties were shown to affect human lifespan, risk of developing bladder cancer, its progression and recurrence under certain conditions.
Subject(s)
Aging/genetics , DNA Helicases/genetics , DNA Repair Enzymes/genetics , Genetic Variation , Neoplasms/genetics , Poly-ADP-Ribose Binding Proteins/genetics , Xeroderma Pigmentosum Group D Protein/genetics , Adult , Age Factors , Aged , Aged, 80 and over , Aging/metabolism , Case-Control Studies , Female , Gene Frequency , Genetic Association Studies , Genetic Predisposition to Disease , Homozygote , Humans , Longevity/genetics , Male , Middle Aged , Neoplasms/enzymology , Neoplasms/pathology , Neoplasms/prevention & control , Phenotype , Prognosis , Protective Factors , Risk FactorsABSTRACT
Genome instability and impaired DNA repair are hallmarks of carcinogenesis. The study was aimed at evaluating the DNA damage response in H2O2-treated lymphocytes using the alkaline comet assay in bladder cancer (BC) patients as compared to clinically healthy controls, elderly persons, and individuals with chronic inflammations. Polymorphism in DNA repair genes involved in nucleotide excision repair (NER) and base excision repair (BER) was studied using the PCR-RFLP method in the Belarusian population to elucidate the possible association of their variations with both bladder cancer risk and clinicopathological features of tumors. The increased level of H2O2-induced DNA damage and a higher proportion of individuals sensitive to oxidative stress were found among BC patients as compared to other groups under study. Heterozygosity in the XPD gene (codon 751) increased cancer risk: OR (95% CI) = 1.36 (1.03-1.81), p = 0.031. The frequency of the XPD 312Asn allele was significantly higher in T ≥ 2 high grade than in T ≥ 2 low grade tumors (p = 0.036); the ERCC6 1097Val/Val genotype was strongly associated with muscle-invasive tumors. Combinations of homozygous wild type alleles occurred with the increased frequency in patients with non-muscle-invasive tumors suggesting that the maintenance of normal DNA repair activity may prevent cancer progression.
Subject(s)
DNA Damage , DNA Helicases/genetics , DNA Repair Enzymes/genetics , DNA Repair , Neoplasm Proteins/genetics , Polymorphism, Restriction Fragment Length , Urinary Bladder Neoplasms/genetics , Xeroderma Pigmentosum Group D Protein/genetics , Adult , DNA Helicases/metabolism , DNA Repair Enzymes/metabolism , Female , Humans , Male , Middle Aged , Neoplasm Invasiveness , Neoplasm Proteins/metabolism , Oxidation-Reduction , Poly-ADP-Ribose Binding Proteins , Urinary Bladder Neoplasms/metabolism , Urinary Bladder Neoplasms/pathology , Xeroderma Pigmentosum Group D Protein/metabolismABSTRACT
CONTEXT: The study of DNA base and nucleotide excision repair gene polymorphisms in bladder cancer seems to have a predictive value because of the evident relationship between the DNA damage response induced by environmental mutagens and cancer predisposition. OBJECTIVE: The objective was to determine OGG1 Ser326Cys, XRCC1 Arg399Gln, XPD Asp312Asn, and ERCC6 Met1097Val polymorphisms in bladder cancer patients as compared to controls. METHODS: Both groups were predominantly represented by Belarusians and Eastern Slavs. DNA samples from 336 patients and 370 controls were genotyped using a PCR-RFLP method. RESULTS: The genotype distributions were in agreement with the Hardy-Weinberg equilibrium. The minor allele frequencies in the control population were in the range of those in Caucasians in contrast to Asians. The OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes were inversely associated with cancer risk (OR [95% CI] = 0.69 [0.50-0.95] and 1.35 [1.0-1.82], respectively). The contrasting effects of these genotypes were potentiated due to their interactions with smoking habit or age. CONCLUSIONS: Among four DNA repair gene polymorphisms, the OGG1 326 Ser/Cys and XPD 312 Asp/Asn heterozygous genotypes might be recognized as potential genetic markers modifying susceptibility to bladder cancer in Belarus.
