Skip to main content

Main menu

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Advertisers
    • Editorial Board
  • Other Publications
    • Anticancer Research
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
  • About Us
    • General Policy
    • Contact
  • Other Publications
    • In Vivo
    • Anticancer Research
    • Cancer Genomics & Proteomics

User menu

  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
In Vivo
  • Other Publications
    • In Vivo
    • Anticancer Research
    • Cancer Genomics & Proteomics
  • Register
  • Subscribe
  • My alerts
  • Log in
  • My Cart
In Vivo

Advanced Search

  • Home
  • Current Issue
  • Archive
  • Info for
    • Authors
    • Advertisers
    • Editorial Board
  • Other Publications
    • Anticancer Research
    • Cancer Genomics & Proteomics
    • Cancer Diagnosis & Prognosis
  • More
    • IIAR
    • Conferences
  • About Us
    • General Policy
    • Contact
  • Visit iiar on Facebook
  • Follow us on Linkedin
Research ArticleExperimental Studies

Investigation of PON1 192 and PON1 55 Polymorphisms in Ovarian Cancer Patients in Turkish Population

AYTAÇ ARPACI, UZAY GÖRMÜŞ, BURAK DALAN, SİNAN BERKMAN and TURGAY ISBİR
In Vivo May 2009, 23 (3) 421-424;
AYTAÇ ARPACI
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
UZAY GÖRMÜŞ
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
BURAK DALAN
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
SİNAN BERKMAN
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
TURGAY ISBİR
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: tisbir@superonline.com
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Background: Ovarian cancer is the leading cause of death due to gynecological malignancies among women. Oxidative stress is potentially harmful to cells and reactive oxygen species are known to be involved in the initiation and progression of cancer. Paraoxonase (PON1) is an antioxidative enzyme, which eliminates lipid peroxides. PON1 has two common polymorphisms (M/L55 and A/B192) that influence PON1 concentration and activity. Patients and Methods: Whether or not the M/L55 or A/B192 genotype relates with ovarian cancer was studied in 51 patients and 54 controls. Polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP), and agarose gel electrophoresis techniques were used to determine these polymorphisms. Results: The proportion of smokers was significantly higher in the patients than the controls (26.9% vs. 7%; Chi-square: 7.81, p:0.005; Odds ratio (OR): 4.88 95% CI: 1.49-15.99). The frequencies of the PON1 192 AA, BB and AB genotypes among the patients were 0.76, 0.12 and 0.12 and among the control subjects, 0.33, 0.11 and 0.56, respectively. The AA genotype frequency was significantly higher in the patients than the controls (Chi-square: 19.242, p=0.000; OR: 2.80 95% CI:1.653-4.757). The frequencies of the PON1 55 LL, MM and LM genotypes among the patients were 0.53, 0.10 and 0.37 and among the control subjects there were 0.46, 0.04 and 0.50, respectively. The MM genotype frequency was higher in the patients than the controls, but not statistically significantly (p>0.05). Conclusion: The two polymorphisms were associated with the age of onset of ovarian cancer, which increased in the genotype order AB<AA<BB in the PON1 192 polymorphism and LM<LL<MM in the PON1 55 polymorphism. The PON1 192 AA genotype may play an important role as a risk factor for ovarian cancer in the Turkish population and the A and L alleles may be associated with early onset of disease.

  • Paraoxonase
  • ovarian cancer
  • polymorphism
  • RFLP
  • PCR

Ovarian cancer is one of the leading causes of death for women worldwide (1). Chemical, dietary, viral, hormonal and genetic factors are thought to contribute to the development of this cancer (1). It had previously been determined that an imbalance between oxidant-antioxidant metabolites caused a tendency to tumor development and it has been suggested that activated oxygen radicals, reactive aldehyde and peroxidases might cause defects in the genes related to the proliferation and differentiation proteins (2-4). It has been shown that high levels of steroid hormones and gonadotrophin exposure increased the risk of ovarian cancer development by increasing lipid peroxidation (5).

Human paraoxanase (PON1), a Ca++-dependent esterase, synthesized in liver, is related to high density lipoprotein (HDL) (6). PON1 has two main roles: detoxifying organophosphate compounds such as paraoxone and protecting LDL by hydrolysis of lipid peroxides (7, 8). Lipid peroxidation has really important roles in the control of the cell cycle (9), in particular polyunsaturated fatty acids (PUFA) are known to be vulnerable to free oxygen radical interaction creating lipid peroxidation (10). The peroxidation products can interact with DNA bases to form exocyclic DNA base products, the most common forms of which are exocyclic pyrimido-purinones which are known to be cytotoxic and mutagenic (11). In tumor cells, there is additional oxidative stress because of rapid metabolism and this is an additional factor causing insufficiency of the antioxidant enzymes (12). As in several other cancer types, the end products of lipid peroxidation have been found to increase and antioxidant enzyme levels to decrease in ovarian cancer patients. It has previously been shown that PON1 gene polymorphisms causing a change from glutamine to arginine at the 192 position and leucine to methionine at the 55 position changed both the level and activity of the enzyme (13-16). Those people with the PON1 192 BB genotype had higher enzyme levels than the PON1 192 AA individuals and the PON1 A allele hydrolysed paraoxone less than the PON1 192 B allele (17).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table I.

Age and body mass index of the study groups (x±SD).

The most common genotypes are in the order AA(QQ), AB(QR), BB(RR) (15,18). It has also been shown that the PON1 55 M allele increased the tendency of proteolysis of this enzyme therefore changing the serum levels (19).

The aim of this study was to determine the PON1 192 and PON1 55 gene polymorphisms in a Turkish population and whether there was any tendency to ovarian cancer created by this polymorphism.

Patients and Methods

Fifty histologically confirmed ovarian cancer patients were diagnosed and followed up in Istanbul University, Department of Obstetrics and Gynecology. Fifty two healthy control subjects were carefully chosen not to have first degree relatives having such a cancer diagnosis. The patient and control groups were matched for age and body mass index (BMI) (Table I). Blood specimens protected with EDTA were taken from all the study subjects.

Polymorphism analysis. A previously reported PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) method was used to determine the PON1 192 and PON1 55 gene polymorphisms (20).

PCR was used to amplify the gene with 5′-TAT TGT TGC TGT GGG ACC TGA G-3′ and 5′-CAC GCT AAA CCC AAA TAC ATC TC-3′ primers for determination of the PON1 192 gene polymorphism and 5′-GAA GAG TGA TGT ATA GCC CCA G-3′ and 5′-TTT AAT CCA GAG CTA ATG AAA GCC-3′ for the PON1 55 polymorphism.

The PCR mixture (total, 25 μl) contained 1-2 μl DNA, 1 μl of each primer, 5 μl dNTP, 1.5 μl of MgCl2 and 0.3 μl Taq polymerase. For the PON1 192 gene polymorphism the mixture was incubated at 95°C for 2 minutes, then 35 cycles of 94°C for 1 minute to denature, 61°C for 1 minute to anneal the primers and 72°C for 1 minute to elongate the strand. After the PCR process, the Alw1 (BspI) restriction enzyme was used and 2% agarose gel electrophoresis was performed to identify the possible polymorphism. Alw1 (BspI) digestion generated the following fragments: PON1 192 B allele, fragments of 66 bp and 33 bp; PON1 192 A allele, a single fragment of 99 bp.

For the determination of the PON1 55 locus polymorphism, the PCR reactions started with incubation of 95°C for 5 minutes and 30 cycles of denaturation for 1 minute at 92°C, followed by annealing for 45 seconds at 52°C and elongation for 45 seconds at 72°C. The restriction enzyme was N1a111 (Hsp192II) for determination of the PON1 55 polymorphism and 2% agarose gel electrophoresis was performed to determine possible polymorphisms. N1a111 (Hsp192II) digestion generated the following fragments: for PON1 55 M allele, fragments of 126 bp and 44 bp; for PON1 55 L allele, a single fragment of 170 bp.

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table II.

PON1 192 genotype and allele distributions in study groups.

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table III.

PON1 55 genotype and allele distributions in study groups.

Statistical analysis. The statistical analyses were conducted using the SPSS 11.0 programme. Chi-square and Fisher's Exact tests were used to determine the differences of the genotypes and alleles between groups.

Results

The PON1 genotype and allele distributions are shown in Table II. The risk of ovarian cancer was 2.8 times higher in the subjects that were not carrying any B allele (subjects with AA genotype) (Chi-square: 19.242, p=0,000; Odds ratio (OD): 2.80 95% CI:1.653-4.757).

View this table:
  • View inline
  • View popup
  • Download powerpoint
Table IV.

PON1 genotype distributions in relation to the starting age of the disease.

The PON1 55 genotype and allele frequencies are given in Table III.

The L (-) subjects were more numerous in the patient group than in the control group but this result was not statistically significant (Chi-square: 1.569, p=0.261 Fisher's exact test).

The relationship of the disease starting age and the polymorphisms was also investigated and the patients with the BB genotype were significantly older than those with the AB genotype (p:0.049). For the PON1 55 genotypes, the starting age of the disease was, in order, MM>LL>LM, but this was not statistically significant (p>0.05) (Table IV).

There were 4 (7%) smoking and 50 (92.6%) non-smoking subjects in control group and 14 (27.4%) smoking and 37 (72.5%) non-smoking subjects in patient group and the risk of developing ovarian cancer in the smokers was 4.8 times higher than in the non-smokers (Chi-square:7.81, p:0.005; OR: 4.88 95% CI: 1.49-15.99).

Discussion

Conflicting results have been reported in previous studies of PON1 polymorphisms and their relationship to cancer. PON1 192 and PON1 55 genotype distributions were found to be similar in colorectal patients group and controls (21). In another study, it was found that PON1 192 AB and PON1 55 LM/MM genotypes had a higher risk of developing prostate cancer in Italian people (22).

In the present study the individuals with the PON1 192 AB genotype developed ovarian cancer earlier than those with the PON1 BB genotype which might be due to a protective effect of the PON1 BB genotype.

In several studies, smoking was found to be related to several kinds of cancer by inhibiting PON1 activity (23-25). In parallel, smoking increased the risk of ovarian cancer development by 4.8 times, in the present study. In a previous study, it was found that the PON1 55 M genotype increased the risk of ovarian cancer development in smokers (25), but a similar result was not found in the present study.

This study was important being the first to assess the relationship of PON1 polymorphisms and ovarian cancer in a Turkish population. The determination of the PON1 activity levels and enlargement of the study is planned groups for future investigations.

  • Received November 26, 2008.
  • Revision received February 18, 2009.
  • Accepted March 17, 2009.
  • Copyright © 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

References

  1. ↵
    1. Levine DA,
    2. Boyd J
    : The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series. Cancer Res 61: 908-911, 2001.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Burdon RH,
    2. Gill V,
    3. Rice Evans C
    : Oxidative stress and tumor cell proliferation. Free Radic Res Commun 11: 65-76, 1990.
    OpenUrlPubMed
    1. Goldstein BD,
    2. Czerniecki B,
    3. Witz G
    : The role of free radicals in tumor promotion. Environ Health Perspect 81: 55-57, 1986.
    OpenUrl
  3. ↵
    1. Dizdaroğlu M
    : Chemical determination of free radical-induced damage to DNA. Free Radic Biol Med 10: 225-242, 1991.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Ness RB,
    2. Cottreau C
    : Possible role of ovarian epithelial inflammation in ovarian cancer. J Nat Cancer Inst 91: 1459-1467, 1999.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Harel M,
    2. Aharoni A,
    3. Gaidukov L,
    4. Brumshtein B,
    5. Khersonsky O,
    6. Meged R,
    7. Dvir H,
    8. Ravelli RB,
    9. McCarthy A,
    10. Toker L,
    11. Silman I,
    12. Sussman JL,
    13. Tawfik DS
    : Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol 11: 412-419, 2004.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Mackness MI,
    2. Mackness B,
    3. Durrington PN,
    4. Fogelman AM,
    5. Berliner J,
    6. Lusis AJ,
    7. Navab M,
    8. Shih D,
    9. Fonarow GC
    : Paraoxonase and coronary heart disease. Curr Opin Lipidol 9(4): 319-324, 1998.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Billecke S,
    2. Draganov D,
    3. Counsell R,
    4. Stetson P,
    5. Watson C,
    6. Hsu C,
    7. La Du BN
    : Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos 28: 1335-1342, 2000.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Diplock AT,
    2. Rice-Evans AC,
    3. Burton RH
    : Is there a significant role for lipid peroxidation in the causation of malignancy and for antioxidants in cancer prevention? Cancer Res 54: 19525-19565, 1994.
    OpenUrl
  9. ↵
    1. Rao MN,
    2. Marmillot P,
    3. Gong M,
    4. Palmer DA,
    5. Seeff LB,
    6. Strader DB,
    7. Lakshman MR
    : Light, but not heavy alcohol drinking, stimulates paraoxonase by up-regulating liver mRNA in rats and humans. Metabolism 52: 1287-1294, 2003.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Martinez G,
    2. Loureiro A,
    3. Marques S,
    4. Miyamoto S,
    5. Yamaguchi LF,
    6. Onuki J,
    7. Almeida EA,
    8. Garcia CC,
    9. Barbosa LF,
    10. Medeiros MH,
    11. Di Mascio P
    : Oxidative and alkylating damage in DNA. Mutat Res 544: 115-127, 2003.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Kenneth AC
    : Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer 37: 1-18, 2000.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Humbert R,
    2. Adler DA,
    3. Disteche CM,
    4. Hassett C,
    5. Omiecinski CJ,
    6. Furlong CE
    : The molecular basis of the human serum paraoxonase polymorphisms. Nat Genet 3: 73-76, 1993.
    OpenUrlCrossRefPubMed
    1. Aviram M,
    2. Hardak E,
    3. Vaya J,
    4. Mahmood S,
    5. Milo S,
    6. Hoffman A,
    7. Billicke S,
    8. Draganov D,
    9. Rosenblat M
    : Human serum paraoxonase (PON1) Q and R selectively decrease lipid peroxides in human coronary and carotid arteriosclerotic lesions. Circulation 101: 2510-2517, 2000.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Mackness BM,
    2. Mackness MI,
    3. Arrol S,
    4. Turkie W,
    5. Durrington PN
    : Effect of the human serum paraoxonase 55 and 192 genetic polymorphisms on the protection by high density lipoprotein against low density lipoprotein oxidative modification. FEBS Lett 423: 57-60, 1998.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Blatter Garin M,
    2. James R,
    3. Dussoix P,
    4. Blanché H,
    5. Passa P,
    6. Froguel P,
    7. Ruiz J
    : Paraoxonase polymorphism Met-Leu54 is associated with modified serum concentrations of the enzyme. A possible link between the paraoxonase gene and increased risk of cardiovascular disease in diabetes. J Clin Invest 99: 62-66, 1997.
    OpenUrlPubMed
  15. ↵
    1. Mackness MI,
    2. Mackness B,
    3. Durrington PN,
    4. Connely PW,
    5. Hegele RA
    : Paraoxonase: biochemistry, genetics and relationship to plasma lipoproteins. Cur Opin Lipid 7: 69-76, 1996.
    OpenUrl
  16. ↵
    1. Aviram M,
    2. Billecke S,
    3. Sorenson R,
    4. Bisgaier C,
    5. Newton R,
    6. Rosenblat M,
    7. Erogul J,
    8. Hsu C,
    9. Dunlop C,
    10. La Du BN
    : Paraoxonase active site required for protection against LDL oxidation involves its free sulfhydryl group and is different from that required for its arylesterase/paraoxonase activities: selective action of human paraoxonase allozymes Q and R. Arterioscler Thromb Vasc Biol 18: 1617-1624, 1998.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Leviev I,
    2. Deakin S,
    3. James R
    : Decreased stability of the M54 isoform of paraoxonase as a contributory factor to variations in human serum paraoxonase concentrations. Journal of Lipid Res 42: 528-535, 2001.
    OpenUrl
  18. ↵
    1. Adkins S,
    2. Gan KN,
    3. Mody M,
    4. La Du BN
    : Molecular basis for the polymorphic forms of human serum paraoxonase/arylesterase: glutamine or arginine at position 191, for the respective A or B allozymes. Am J Hum Genet 52: 598-608, 1993.
    OpenUrlPubMed
  19. ↵
    1. Van Der Logt EM,
    2. Janssen CH,
    3. Van Hooijdonk Z,
    4. Roelofs HM,
    5. Wobbes T,
    6. Nagengast FM,
    7. Peters WH
    : No association between genetic polymorphisms in NAD(P)H oxidase p22phox and paraoxonase 1 and colorectal cancer risk. Anticancer Res 25: 1465-1470, 2005.
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Antognelli C,
    2. Mearini L,
    3. Talesa VN,
    4. Giannantoni A,
    5. Mearini E
    : Association of CYP17, GSTP1, and PON1 polymorphisms with the risk of prostate cancer. Prostate 63: 240-251, 2005.
    OpenUrlPubMed
  21. ↵
    1. Ferre N,
    2. Camps J,
    3. Fernandez-Ballart J,
    4. Arija V,
    5. Murphy MM,
    6. Ceruelo S
    : Regulation of serum paraoxonase activity by genetic, nutritional and lifestyle factors in the general population. Clin Chem 49: 1491-1497, 2003.
    OpenUrlAbstract/FREE Full Text
    1. Senti M,
    2. Tomas M,
    3. Anglada R,
    4. Elosua R,
    5. Marrugat J,
    6. Covas MI
    : Inter-relationship of smoking, paraoxonase activity, and leisure time physical activity: a population-based study. Eur J Int Med 14: 178-184, 2003.
    OpenUrl
  22. ↵
    1. Lurie G,
    2. Wilkens LR,
    3. Thompson PJ,
    4. McDuffie KE,
    5. Carney ME,
    6. Terada KY,
    7. Goodman MT
    : Genetic polymorphisms in the paraoxonase 1 gene and risk of ovarian epithelial carcinoma. Cancer Epidemiol Biomarkers Prev 17: 2070-2077, 2008.
    OpenUrlAbstract/FREE Full Text
PreviousNext
Back to top

In this issue

In Vivo: 23 (3)
In Vivo
Vol. 23, Issue 3
May-June 2009
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
  • Back Matter (PDF)
  • Front Matter (PDF)
Print
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for your interest in spreading the word on In Vivo.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Investigation of PON1 192 and PON1 55 Polymorphisms in Ovarian Cancer Patients in Turkish Population
(Your Name) has sent you a message from In Vivo
(Your Name) thought you would like to see the In Vivo web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
2 + 0 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
Investigation of PON1 192 and PON1 55 Polymorphisms in Ovarian Cancer Patients in Turkish Population
AYTAÇ ARPACI, UZAY GÖRMÜŞ, BURAK DALAN, SİNAN BERKMAN, TURGAY ISBİR
In Vivo May 2009, 23 (3) 421-424;

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Reprints and Permissions
Share
Investigation of PON1 192 and PON1 55 Polymorphisms in Ovarian Cancer Patients in Turkish Population
AYTAÇ ARPACI, UZAY GÖRMÜŞ, BURAK DALAN, SİNAN BERKMAN, TURGAY ISBİR
In Vivo May 2009, 23 (3) 421-424;
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Patients and Methods
    • Results
    • Discussion
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • Q192R and L55M Polymorphisms of Paraoxonase 1 Gene in Chronic Myelogenous Leukemia and Chronic Lymphocytic Leukemia
  • The Effects of PON1 Gene Q192R Variant on the Development of Uterine Leiomyoma in Turkish Patients
  • Paraoxonase-1 192/55 Polymorphisms and the Risk of Lung Cancer in a Turkish Population
  • Google Scholar

More in this TOC Section

  • Learning Needle Placement in Soft Tissue With Robot-assisted Navigation
  • Changes in Lactate-related Fecal Microbiome in Hyperlactatemia Diabetic Dogs
  • Effects of Irradiation by Carbon Dioxide Laser Equipped With a Water Spray Function on Bone Formation in Rat Tibiae
Show more Experimental Studies

Similar Articles

In Vivo

© 2023 In Vivo

Powered by HighWire