RESEARCH PAPER
Searching for in vitro biomarkers of susceptibility to prostate and cervical cancers by analysis of chromosomal instability, γ-H2AX foci, polymorphisms in DNA repair genes and apoptosis
1
Department of Radiobiology and Immunology, Institute of Biology, Jan Kochanowski University, Kielce, Poland
2
Department of Microbiology, Institute of Biology, Jan Kochanowski University, Kielce, Poland
3
Cancer Centre, Kielce, Poland
4
Endomedical-Diagnostic and Therapeutic Centre for Diseases of the Digestive Tract, Kielce, Poland
5
Institute of Public Health, Jan Kochanowski University, Kielce, Poland
6
MBW Department, Stockholm University, Stockholm, Sweden
7
Faculty of Automatic Control, Electronics and Computer Science, Silesian University of Technology, Gliwice, Poland
8
Centre for Radiobiology and Biological Dosimetry, Institute of Nuclear Chemistry and Technology, Warsaw, Poland
Corresponding author
Anna Lankoff
Department of Radiobiology and Immunology, Institute of Biology, Jan Kochanowski University, Swietokrzyska 15, 25-406 Kielce, Poland
Department of Radiobiology and Immunology, Institute of Biology, Jan Kochanowski University, Swietokrzyska 15, 25-406 Kielce, Poland
J Pre Clin Clin Res. 2015;9(2):97–104
KEYWORDS
Cervical cancer patientsprostate cancer patientshealthy donorshuman lymphocyteschromosomal instabilityγ-H2AX fociApoptosisionizing radiationSNP (single nucleotide polymorphisms)
ABSTRACT
Introduction and objective.:
According to the cancer epidemiology databases, cancer is the second leading cause of death in developing countries. Moreover, the WHO predicts a continuing increase in the incidence of cancer, extending this trend well into the next several decades. Hence, it seems obvious that the prediction of cancer susceptibility and early diagnosis is an important goal for modern biomedical sciences. The aim of this study is to clarify the value of chromosomal damage, capacity for the repair of double-strand breaks (DSBs), polymorphisms in DNA repair genes, and apoptosis as prognostic markers for prostate and cervical cancer.
Material and Methods:
30 prostate cancer patients and 30 cervical cancer patients were enrolled into the study. In addition, 30 healthy female donors and 30 healthy male donors served as controls. The following endpoints were investigated: frequency of micronuclei, gamma-H2AX fluorescence, XRCC1 194C>T, XRCC1 399G>A, XRCC3 IVS5–14 A>G, OGG1 326 Ser>Cys polymorphisms and apoptosis
Results:
Among all tested factors, only the homozygous variant (Arg/Arg) in XRCC1 (399 Arg/Gln) was strongly associated with prostate cancer risk, and only a low apoptotic response was connected with cervical cancer risk. The presented study confirmed a positive association between the frequency of MN and increased prostate and cervical cancer risk. However, such a biomarker is not cancer specific. In addition, the information gained by analyzing the gamma-H2AX fluorescence, as well apoptosis, had no value for predicting the risk of prostate and cervical cancers.
Conclusions:
The final conclusion of the study is that cancer susceptibility is a complex phenotype not readily detectable in relatively small studies by functional assays or analysis of SNP in few, selected genes.
According to the cancer epidemiology databases, cancer is the second leading cause of death in developing countries. Moreover, the WHO predicts a continuing increase in the incidence of cancer, extending this trend well into the next several decades. Hence, it seems obvious that the prediction of cancer susceptibility and early diagnosis is an important goal for modern biomedical sciences. The aim of this study is to clarify the value of chromosomal damage, capacity for the repair of double-strand breaks (DSBs), polymorphisms in DNA repair genes, and apoptosis as prognostic markers for prostate and cervical cancer.
Material and Methods:
30 prostate cancer patients and 30 cervical cancer patients were enrolled into the study. In addition, 30 healthy female donors and 30 healthy male donors served as controls. The following endpoints were investigated: frequency of micronuclei, gamma-H2AX fluorescence, XRCC1 194C>T, XRCC1 399G>A, XRCC3 IVS5–14 A>G, OGG1 326 Ser>Cys polymorphisms and apoptosis
Results:
Among all tested factors, only the homozygous variant (Arg/Arg) in XRCC1 (399 Arg/Gln) was strongly associated with prostate cancer risk, and only a low apoptotic response was connected with cervical cancer risk. The presented study confirmed a positive association between the frequency of MN and increased prostate and cervical cancer risk. However, such a biomarker is not cancer specific. In addition, the information gained by analyzing the gamma-H2AX fluorescence, as well apoptosis, had no value for predicting the risk of prostate and cervical cancers.
Conclusions:
The final conclusion of the study is that cancer susceptibility is a complex phenotype not readily detectable in relatively small studies by functional assays or analysis of SNP in few, selected genes.
REFERENCES (41)
1.
Hagmar L, Bonassi S, Strömberg U, Mikoczy Z, Lando C, Hansteen I-L, Montagud AH, Knudsen L, Norppa H, Reuterwall Ch, Tinnerberg H, Brøgger A, Forni A, Högstedt B, Lambert B, Mitelman F, Nordenson I, Salomaa S, Skerfving S. Canser predictive value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the Europen Study on Cytogenetic. Mutat Res. 1998; 405: 171–178.
2.
Bonassi S, Hagmar L, Stromberg U, Montagud AH, Tinnerberg H, Forni A, Heikkila P, Wanders S, Wilhardt P, Hansteen IL, Knudsen LE and Norppa H. Chromosomal aberrations in lymphocytes predict human cancer independently of exposure to carcinogens. Cancer Res. 2000; 60: 1619–1625.
3.
Spitz MR, Hsu TC. Mutagen sensitivity as a marker of cancer risk. Cancer Detect Prev. 1994; 18: 299–303.
4.
Sanford KK, R Parshad R, Gatt RE, Tarone GM, Jonem IF, M Price. Factors affecting and significance of G2 chromatin radiosensitivity in predisposition to cancer. Int J Radiat Biol. 1989; 55: 963–981.
5.
Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 2002; 11: 1513–1530.
6.
Xu Y, He B, Li R, Pan Y, Gao T, Deng Q, Sun H, Song G, Wang S. Association of the polymorphisms in the Fas/FasL promoter regions with cancer susceptibility: a systematic review and meta-analysis of 52 studies. PLoS One 2014 Mar 5; 9(3): e90090. doi: 10.1371/journal.pone.0090090. eCollection 2014.
7.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61: 69–90.
9.
Darzynkiewicz Z, Bruno S, Del Bino G, Gorczyca W, Hotz MA, Lassota P, Traganos F. Features of apoptotic cells measured by flow cytometry. Cytometry 1992; 13: 795–808.
10.
Faul F, Erdfelder E, Lang AG, Buchner A. G*Power3: A flexible statistical power analysis program for the social, behavioral and biomedical sciences. Behavior Res Methods 2007; 39: 175–191.
11.
Rosner B. Fundamentals of biostatistics. 7th edition, Cengage Learning Inc. 2010.
12.
Fenech M. Cytokinesis-block micronucleus assay evolves into a “cytome” assay of chromosomal instability, mitotic dysfunction and cell death. Mutat Res. 2006; 600: 58–66.
13.
Venkatachalam P, Paul SF, Mohankumar MN, Prabhu BK, Gajendiran N, Kathiresan A, Jeevanram RK. Higher frequency of dicentrics and micronuclei in peripheral blood lymphocytes of cancer patients. Mutat Res. 1999; 425: 1–8.
14.
Chakrabarti RN, Dutta K. Micronuclei test in routine smears from uterine cervix. Eur J Gynaecol Oncol. 1998; 9: 370–2.
15.
Cerqueira EM, Santoro CL, Donozo NF, Freitas BA, Pereira CA, Bevilacqua RG, Machado-Santelli GM. Genetic damage in exfoliated cells of the uterine cervix. Association and interaction between cigarette smoking and progression to malignant transformation? Acta Cytol. 1998; 42: 639–49.
16.
Leal-Garza CH, Cerda-Flores RM, Leal-Elizondo E, Cortés-Gutiérrez EI. Micronuclei in cervical smears and peripheral blood lymphocytes from women with and without cervical uterine cancer. Mutat Res. 2002; 515: 57–62.
17.
Milosević-Djordjević O, Grujiciĉ D, Vaskoviĉ Z, Marinkoviĉ D. High micronucleus frequency in peripheral blood lymphocytes of untreated cancer patients irrespective of gender, smoking and cancer sites. Tohoku J Exp Med. 2010; 220: 115–20.
18.
Bonassi S, Fenech M, Lando C, Lin YP, CePMi M, Chang WP, Holland N, Kirsch-Volders M, Zeiger E, Ban S, Barale R, Bigatti MP, Bolognesi C, Jia C, Di Giorgio M, Ferguson LR, Fucic A, Lima OG, Hrelia P, Krishnaja AP, Lee TK., Migliore L, Mikhalevich L, Mirkova E, Mosesso P, Müller WU, Odagiri Y, Scarffi MR, Szabova E, Vorobtsova I, Vral A, Zijno A. HUman MicroNucleus project: international database comparison for results with the cytokinesis-block micronucleus assay in human lymphocytes: I. Effect of laboratory protocol, scoring criteria, and host factors on the frequency of micronuclei. Environ Mol Mutagen. 2001; 37: 31–45.
19.
Iliakis G, Wang H, Perrault AR, Boecker W, Rosidi B, Windhofer F, Wu W, Guan J, Terzoudi G, Pantelias G. Mechanisms of DNA double strand break repair and chromosome aberration formation. Cytogenet Genome Res. 2004; 104: 14–20.
20.
Fernandez-Capetillo O, Lee A, Nussenzweig M, Nussenzweig A. H2AX: the histone guardian of the genome. DNA Repair. 2004; 3: 959–967.
21.
Olive PL, Banáth JP, Keyes M. Residual gamma-H2AX after irradiation of human lympocytes and monocytes in vitro and its relation to late effects after prostate brachyterapy. Radiother Oncol. 2008; 86: 336–346.
22.
Brzozowska K, Pinkawa M, Eble MJ, Müller WU, Wojcik A, Kriehuber R, Schmitz S. In vivo versus in vitro individual radiosensitivity analysed in healthy donors and in prostate cancer patients with and without severe side effects after radiotherapy. Int J Radiat Biol. 2012; 88: 405–413.
23.
Kotsopoulos J, Chen Z, Vallis KA, Poll A, Ainsworth P, Narod SA. DNA repair capacity as a possible biomarker of breast cancer risk in female BRCA1 mutation carriers. Br J Cancer 2007; 15: 118–25.
24.
Xu E, Gong Y, Gu J, Jie L, Ajani JA, Wu X. Risk assessment of esophageal adenocarcinoma using γ-H2AX assay. Cancer Epidemiol Biomarkers Prev. 2013; 22: 1797–804.
25.
Fernández MI, Gong Y, Ye Y, Lin J, Chang DW, Kamat AM, Wu X. γ-H2AX level in peripheral blood lymphocytes as a risk predictor for bladder cancer. Carcinogenesis 2013; 34: 2543–7.
26.
Park JY, Park JM, Jan, JS, Choi JE, Kim KM, Cha SI, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Lee JT, Jung TH. Caspase 9 promoter polymorphisms and risk of primary lung cancer. Hum Mol Genet. 2006; 15: 1963–71.
27.
Crompton NE, Miralbel R, Rutz HP, Ersoy F, Sanal O, Wellmann D, Bieri S, Coucke PA, Emery GC, Shi YQ, Blattmann H, Ozsahin M. Altered apoptotic profiles in irradiated patients with increased toxicity. Int J Radiat Oncol Biol Phys. 1999; 45: 707–14.
28.
Docherty Z, Georgiou A, Langman C, Kesterton I, Rose S, Camplejohn R, Ball J, Barwell J, Gilchrist R, Pangon L, Berg J, Hodgson S. Is chromosome radiosensitivity and apoptotic response to irradiation correlated with cancer susceptibility? Int J Radiat Biol. 2007; 83: 1–12.
29.
Camplejohn RS, Gilchrist R, Easton D, McKenzie-Edwards E, Barnes DM, Eccles DM, Ardern-Jones A, Hodgson SV, Duddy PM, Eeles RA. Apoptosis, ageing and cancer susceptibility. Br J Cancer 2003; 24: 487–90.
30.
Hamano T, Matsui H, Ohtake N, Nakata S, Suzuki K. Polymorphisms of DNA repair genes, XRCC1 and XRCC3, and susceptibility to familiar prostate cancer in a Japanese population. Asia Pac J Clin Oncol. 2008; 4: 21–26.
31.
van Gils CH, Bostick RM, Stern MC, Taylor JA. Differences in base excision repair capacity may modulate the effect of dietary antioxidant intake on prostate cancer risk: an example of polymorphisms in the XRCC1 gene. Cancer Epidemiol Biomarkers Prev. 2002; 11: 1279–84.
32.
Rybicki BA, Conti DV, Moreira A, Cicek M, Casey G, Witte JS. DNA repair gene XRCC1 and XPD polymorphisms and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2004; 13: 23–9.
33.
Ritchey JD, Huang WY, Chokkalingam AP, Gao YT, Deng J, Levine P, Stanczyk FZ, Hsing AW. Genetic variants of DNA repair genes and prostate cancer: a population – based study. Cancer Epidemiol Biomarkers Prev. 2005; 14: 1703–9.
34.
Chen L, Ambrosone CB, Lee J, Sellers TA, Pow-Sang J, Park JY. Association between polymorphisms in the DNA repair genes XRCC1 and APE1, and the risk of prostate cancer in white and black Americans. J Urol. 2006; 175: 108–12.
35.
Hirata H, Hinoda Y, Kikuno N, Kawamoto K, Dahiya AV, Suehiro Y, Tanaka Y, Dahiya R. CXCL12 G801A polymorphism is a risk factor for sporadic prostate cancer susceptibility. Clin Cancer Res. 2007; 13: 5056–62.
36.
Geng J, Zhang Q, Zhu C, Wang J, Chen L. XRCC1 genetic polymorphism Arg399Gln and prostate cancer risk: a meta-analysis. Urology 2009; 74: 648–83.
37.
Zhang H, Xu Y, Zhang Z, Li L. The hOGG1 Ser326Cys polymorphism and prostate cancer risk: a meta-analysis of 2584 cases and 3234 controls. BMC Cancer 2011; 13: 11–391.
38.
Mandal RK, Kapoor R, Mittal RD. Polymorphic variants of DNA repair gene XRCC3 and XRCC7 and risk of prostate cancer: a study from North Indian population. DNA Cell Biol. 2010; 29: 669–74.
39.
Mei J, Duan HX, Wang LL, Yang S, Lu JQ, Shi TY, Zhao Y. XRCC1 polymorphisms and cervical cancer risk: an updated meta-analysis. Tumour Biol. 2014; 35: 1221–1231.
40.
Farkasova T, Gurska S, Witkovsky V, Gabelova A. Significance of amino acid substitution variants of DNA repair genes in radiosusceptibility of cervical cancer patients; a pilot study. Neoplasma 2008; 55: 330–7.
41.
Niu Y, Zhang X, Zheng Y, Zhang R. XRCC1 deficiency increased the DNA damage induced by γ-ray in HepG2 cell: Involvement of DSB repair and cell cycle arrest. Environ Toxicol Pharmacol. 2013; 36: 311–319.
Share
RELATED ARTICLE
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.