CEBP Infection and Cancer: Biology, Therapeutics, and Prevention Translational Cancer Medicine 2008: Cancer Clinical Trials and Personalized Medicine
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sehouli, J.
Right arrow Articles by Lichtenegger, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sehouli, J.
Right arrow Articles by Lichtenegger, W.
Cancer Epidemiology Biomarkers & Prevention Vol. 12, 1205-1208, November 2003
© 2003 American Association for Cancer Research

Interleukin-1 Receptor Antagonist Gene Polymorphism in Epithelial Ovarian Cancer

Jalid Sehouli, Alexander Mustea, Dominique Koensgen and Werner Lichtenegger

Department of Obstetrics and Gynaecology, Charité, Humboldt University, Berlin, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The development of malignant tumors is constituted by different immunological components. Interleukin (IL)-1 receptor antagonist (RA) is known to be critically involved in the carcinogenesis of different malignant solid tumors. Polymorphism of a specific gene can have an important effect on gene transcription, the stability of the mRNA, or the quantity and activity of the resulting protein. In a case-control study, we investigated the polymorphism of the IL-1RA gene in 162 women with histologically proven ovarian cancer and 121 patients with benign gynecological diseases. Overall, 25.9% of the patients were diagnosed in International Federation of Gynecologists and Obstetricians (FIGO) stage I or II, and 74.1% of the patients were diagnosed in FIGO stage III or IV (study group). The distribution of genotype frequencies was significantly different between study and control group with respect to allele 1/2 heterozygotes (32.1% versus 14.9%; P < 0.001). Furthermore, patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk for ovarian cancer with an odds ratio of 2.7 (95% confidence interval, 1.5–4.9). There were no differences between IL-1 RA 1/2 polymorphism and other alleles in clinical parameters (e.g., tumor stage, histological type, and recurrence status). Allele 2 polymorphism of the IL1-RA gene seems to be one of the critical points in the molecular pathway of different malignant diseases. This allele seems to play an additional role in the occurrence of ovarian cancer and should be further investigated for screening and risk evaluation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ovarian cancer is the leading cause of death of all of the gynecological malignancies (1) . The overall 5-year survival rate remains poor, despite significant improvements in surgical treatment and chemotherapy (2 , 3) .

More than 75% of all patients are classified as being FIGO1 stage III and IV at the time of diagnosis (4) .

Over the last decade, ovarian cancer screening using the serum marker CA-125 and transvaginal ultrasound examination has been investigated, but none of these methods fulfills the necessary criteria to be considered as an effective screening test (5) . Therefore, new predictive and prognostic factors for ovarian cancer are needed to inprove clinical management.

Unlike gene mutations, polymorphisms in specific genes are common genetic events. It is estimated that there are approximately 200,000 single-nucleotide polymorphisms within the coding regions of the 80,000 human genes (6 , 7) . These could be either a single-bp substitution of one nucleotide for another or a variable repeated number of a short, repetitive DNA sequences (8) .

These variations may affect the rate of gene transcription, the stability of the mRNA, or the quantity and activity of the resulting protein.

The prevalence and severity of a number of disorders will be influenced by certain polymorphic genes possessing specific alleles (7) .

The polymorphic gene that encodes the IL-1 RA seems to play an important role in the development of different diseases (8) .

IL-1 RA belongs to the IL-1 family, which consists of three linked genes mapping within a 430-kb region of the long arm of chromosome 2 in humans, encoding the secreted glycoproteins IL-1 {alpha}, IL-1 ß, and IL-1 RA. All three molecules bind to IL-1 receptors (9, 10, 11) . IL-1{alpha} and IL-1ß are potent proinflammatory cytokines, whereas IL-1 RA as an anti-inflammatory cytokine competes with IL-1{alpha} and IL-1ß in binding to IL-1 receptors without intrinsic effect (12 , 13) .

Polymorphisms have been reported in all three genes (12) . The polymorphism of IL-1{alpha}, IL-1ß, and IL-1 RA produces alterations of IL-1{alpha}, IL-1ß, and IL-1 RA protein expression (14, 15, 16, 17, 18, 19) , and it may have crucial effects on oncogenic processes (20) .

The role of IL-1 RA in ovarian carcinogenesis is currently being investigated. IL-1 increases the growth of ovarian carcinoma cell lines (21) and tumor proliferation (22) . Furthermore, different studies reported an association of IL-1 gene polymorphisms with gastric, pancreatic, and cervical cancer (23, 24, 25, 26) .

Based on these data, we analyzed the influence of IL-RA polymorphism on the prevalence of ovarian cancer and its correlation with established clinical prognostic factors.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This case-control, mono-institution study was reviewed and approved by the Clinical Review Board and Ethics Committee of the University Hospital, Charité, Berlin, Germany.

Patients with histologically confirmed ovarian cancer were allocated to this trial. Written informed consent was provided by each patient. Borderline ovarian tumors are different tumor entities and therefore were excluded from this study (27) .

Germ-line mutations do not fluctuate with age, and the control group consisted of similarly aged women with no history of cancer (4) . The characteristics of the control group are summarized in Table 1Citation . None of these women had previous oophorectomy. To avoid confounding by genetic admixture, only white Caucasian women were enrolled in this study.


View this table:
[in this window]
[in a new window]
  		Table 1 Characteristics of the control group

 
Genetic Studies.
Two ml of blood were drawn from the antecubital vein, and DNA was extracted using the Qiagen System (QIAamp DNA Blood Midi Kit, Hilden, Germany).

DNA was stored at 4°C until analyzed. A genomic DNA fragment was amplified by the PCR to determine IL-1 RA genotypes.

Oligonucleotide primers flanking the 86-bp repeat region in intron 2 of IL-1 RA were applied. The sequence of the forward primer was 5'-CTCAGCAACACTCCTAT-3'. The reverse primer sequence was 5'-TCCTGGTCTGCAGGTAA-3' (28) .

PCR conditions included an initial denaturing step at 94°C for 5 min, followed by 30 cycles of 94°C for 1 min, 60°C for 1 min, and 70°C for 2 min, and a final extension at 70°C for 4 min.

Using this PCR strategy, the common allele (allele 1) generated a 410-bp band (including four copies of an 86-bp repeat). The uncommon alleles generated a 240-bp band (two copies of the same repeat; allele 2) a 500-bp band (five copies of the same repeat; allele 3), and a 325-bp band (allele 4).

PCR products were resolved on a 3% agarose gel and stained with SYBR Green I (FMC Bio Products Europe, Vallensbaek Strand, Denmark).

Statistics.
SPSS (version 10.0; SPSS Inc., Chicago, IL) for Windows statistical software was used for statistical analyses. Differences in the frequencies of IL-1 RA alleles in the groups were analyzed by the two-tailed Fisher’s exact test. All Ps were two-tailed. P < 0.05 was considered statistically significant. Odds ratios with 95% confidence intervals were calculated.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
From June 2001 to April 2003, 179 women with ovarian cancer who were treated in the University Hospital, Charité were enrolled into this study.

All patients with a histologically confirmed diagnosis and written informed consent were included.

DNA extraction was not possible because of technical reasons in two cases. Fifteen patients were excluded from this study because of different histological diagnosis (borderline tumor of the ovary, colon carcinoma). Overall, 162 women with ovarian cancer and 121 women with no history of cancer were analyzed.

The characteristics of the women with ovarian cancer are summarized in Table 2Citation . The median age of the patients with ovarian cancer was 56 years (range, 26–81 years). Of 162 patients, only 16% were diagnosed in FIGO stage I; 77.2% were in FIGO stage III-IV. The most common histological type was serous-papillary (74.7%). To enhance the relevance of the statistics, the following subgroups were summarized: for statistical analysis, stage I + II and III + IV; for histological grading, grading I + II and grading III + IV. No statistically significant differences were observed between the study and control groups with regard to allele 1/3 (2.4% versus 0.6%; P = 0.3) or homozygous allele (IL-1RA 1/1; 74% versus 63.6%; P = 0.07).


View this table:
[in this window]
[in a new window]
  		Table 2 Characteristics of the ovarian cancer group

 
With regard to allele 1/2 heterozygotes, the distribution of genotype frequencies was significantly different between the study and control groups (32.1% versus 14.9%; P < 0.001). Patients who were heterozygous at allele 2 for IL-1 RA (IL-RA 1/2) had a significantly higher risk for ovarian cancer with a calculated odds ratio of 2.7 (95% CI, 1.5–4.9).

The allele frequencies of IL-RA wild-type and polymorphic alleles in the study and control groups are given in Table 3Citation .


View this table:
[in this window]
[in a new window]
  		Table 3 Allele frequencies of IL-RA among women with ovarian cancer and control group

 
We compared all relevant clinical data of the patients with ovarian cancer and allele 2 heterozygote genotype (IL-RA 1/2) with patients of the other genotypes in the cancer group. No statistically significant differences were found in the correlation between IL-1 RA 1/2 polymorphism and FIGO stage (P = 0.3), histological grading (P = 0.22), recurrence status (P = 0.32) ascites volume (<=500 ml versus >=500 ml; P = 0.8), residual tumor mass (P = 0.13), and age (P = 0.8).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
IL-1 RA may have a function in the host immune responses in the local and general environments of gynecological cancers (29) . IL-1RA decreases tumor growth and tumor angiogenesis (30) .

Polymorphisms exist in all three genes of the IL-1 family (IL-1{alpha}, IL-1ß, and IL-1RA) and are located very close each to other on the long arm of human chromosome 2q (31 , 32) . The mutation in one of these genes up-regulates the expression of these genes, e.g., IL-1 RA polymorphism is associated with enhanced IL-1ß production in vitro (16) . Also, IL-1 RA genotype plays a major role as a modulator in IL-1ß release (33) .

Allele 2 of IL-1 RA seems to be the critical point in the molecular pathway of different diseases. The two-repeat allele has been associated with different benign diseases [vestibulitis, ulcerative colitis, alopecia areata, psoriasis, and autoimmune conditions (6 , 34) ] and idiopathic recurrent miscarriage (35) . There are new data that indicate an additional role in cancer.

El-Omar et al. (23) and Machado et al. (36) have reported an association of the IL-1 gene cluster polymorphism with enhanced production of IL-1ß and gastric cancer. Carriers of IL-1 1B-511T and allele 2 of IL-1 RA homozygotes had an increased risk of developing gastric cancer, with odds ratios of 2.7 (95% CI, 1.5–4.9) and 3.1 (95% CI, 1.5–6.5), respectively. Their findings complement the most widely accepted multistage model of gastric carcinogenesis and underline the fact that host genetic factors may determine why some people infected with Helicobacter pylori develop gastric cancer, whereas others do not (23 , 36) .

This hypothesis can be transferred and applied to other solid tumors. Recently, we have published that IL-1 RA is also associated with cervical cancer. Allele 2 heterozygotes have a greater risk of developing cervical cancer [P = 0.04 (37 , 25) ].

In our study, we have demonstrated that allele 2 polymorphism of the IL-RA gene is significantly associated with ovarian cancer. Allelic frequencies were different between patients with ovarian cancer and controls. Patients who are heterozygotes at allele 2 for IL-1 RA (IL-RA 1/2) have a significantly higher risk of ovarian cancer with an odds ratio of 2.7 (95% CI, 1.5–4.9). However, IL-1 RA polymorphism seems to give no information about the prognosis of the patients. We have not observed any association between specific alleles and clinical features such as FIGO stage, histological type, or grading. Nevertheless, the impact of an allele 1/2 polymorphism on progression-free survival and overall survival should be investigated.

Recently, Hefler et al. (38) published a case-control study in which IL-1 gene cluster was genotyped in 94 ovarian cancer patients and 27 patients with borderline ovarian tumors and 134 healthy women.

In contrast to our results, they found no differences in the prevalence of polymorphisms in the IL-1 RA gene between the ovarian cancer and control groups. The distribution of tumor stage of the enrolled patients in our study was different: stage I, 16% versus 40.8%; stage II, 6.8% versus 12.7%; and stage III-IV, 77.2% versus 45.6%. The histological type of ovarian cancer determines tumor biology and is an important prognostic factor. For instance, cytogenetic alterations in ovarian clear cell carcinoma exist and might be the cause of the poorer prognosis of these patients (39) . In the study of Hefler and co-workers, the rates of clear cell carcinoma and endometrioid adenocarcinoma were significantly higher compared with our study (11% versus 3.1%, respectively; 30.8% versus 4.9%). This could be an explanation for the different results we have observed.

The possible limitations of studies with small sample size concerning the statistical validity should be kept in mind when interpreting the results of this study. Ovarian cancer is known to be a polygenic disease, and genetic factors must play an additional role in the induction of this malignancy, whereas only some of the genes were identified in ovarian cancer patients. Maybe some of them can mask potential influences of IL-1 RA polymorphism in ovarian cancer. Therefore, the presented data should be confirmed within a panel of polymorphic genes that are associated with ovarian cancer, such as androgen receptor gene (40) , MTHFR gene (41) , or cyclin D1 gene (3) in a prospective cohort study of patients with allele 1/2 polymorphism concerning the risk for developing ovarian cancer.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Alexander Mustea, Charité, Department of Obstetrics and Gynaecology, Humboldt University, Augustenburger Platz 1, D- 13353 Berlin, Germany. Phone: 49-30-450564052; Fax: 49-30-450564952; E-mail: amustea{at}yahoo.com

1 The abbreviations used are: FIGO, International Federation of Gynecologists and Obstetricians; IL, interleukin; RA, receptor antagonist; CI, confidence interval. Back

Received 2/28/03; revised 7/29/03; accepted 8/ 6/03.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Landis S. H., Murray T., Bolden S. Cancer statistic. CA Cancer J. Clin., 8: 49-54, 1999.
  2. Chang J., Bridgewater J., Gore M. Non-surgical aspects of ovarian cancer. Lancet, 343: 335-341, 1994.[Medline]
  3. Dhar K., Branigan K., Howells R., Musgrove C., Jones P. W., Strange R. C., Fryer A. A., Redman C. W., Hoban P. R. Prognostic significance of cyclin D1 gene (CCND1) polymorphism in epithelial ovarian cancer. Int. J. Gynecol. Cancer, 9: 342-347, 1999.[Medline]
  4. Lichtenegger W., Sehouli J., Buchmann E., Karajanev C., Weidemann H. Operative results after primary and secondary debulking-operations in advanced ovarian cancer (AOC). J. Obstet. Gynaecol. Res., 24: 447-451, 1998.[Medline]
  5. Schrecengost A. Ovarian mass: benign or malignant?. AORN J., 76: 792-802, 2002.[Medline]
  6. Jeremias J., Ledger W. J., Witkin S. Interleukin 1 receptor antagonist gene polymorphism in women with vulvar vestibulitis. Am. J. Obstet. Gynecol., 182: 283-285, 2000.[Medline]
  7. Strauss J. F. Unravelling the genetics of complex disorders of reproduction Countinuto E. M. Spinola P. eds. . Reproductive Medicine: A Millennium Review, 284-287, The Parthenom Publishing Group New York 1999.
  8. Witkin S. S., Gerber S., Ledger W. J. Influence of interleukin-1 receptor antagonist gene polymorphism on disease. Clin. Infect. Dis., 34: 204-209, 2002.[Medline]
  9. Dinarello C. A. Biologic basis for interleukin-1 in disease. Blood, 87: 2095-2147, 1996.[Abstract/Free Full Text]
  10. Iizuka N., Hazama S., Hirose K. Interleukin 1 receptor antagonist mRNA expression and the progression of gastric carcinoma. Cancer Lett., 142: 179-184, 1999.[Medline]
  11. Eisenberg S. P., Brewer M. T., Verderber E., Heimdal P., Brandhuber B. J., Thompson R. C. Interleukin-1 receptor antagonist is a member of the interleukin 1 gene family. Evolution of a cytokine control mechanism. Proc. Natl. Acad. Sci. USA, 88: 5232-5236, 1991.[Abstract/Free Full Text]
  12. Dinarello C. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Intern. Rev. Immunol., 16: 457-499, 1998.[Medline]
  13. Arend W. P. Interleukin 1 receptor antagonist: discovery, structure and properties. Prog. Growth Factor Res., 2: 193-205, 1990.[Medline]
  14. Danis V. A., Millington M., Hyland V. J., Grennan D. Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. Clin. Exp. Immunol., 99: 303-310, 1995.[Medline]
  15. Hurme M., Santtila S. IL-1 receptor antagonist (IL-1Ra) plasma levels are co-ordinately regulated by both IL-1Ra and IL-1ß genes. Eur. J. Immunol., 28: 2598-2602, 1998.[Medline]
  16. Santtila S., Savinainen K., Hurme M. Presence of the IL-1RA allele 2 (IL1RN*2) is associated with enhanced IL-1ß production in vitro. Scand. J. Immunol., 47: 195-198, 1998.[Medline]
  17. Pociot F., Molvig J., Wogensen L., Worsaae H., Nerup J. A. TaqI polymorphism in the human interleukin-1 ß (IL-1 ß) gene correlates with IL-1 ß secretion in vivo. Eur. J. Clin. Investig., 22: 396-402, 1992.[Medline]
  18. Licastro F., Pedrine S., Ferri C., Casadei V., Govoni M., Pession A., Sciacca F. L., Veglia F., Annoni G., Bonafe M., Olivieri F., Franceschi C., Grimaldi L. M. Gene polymorphism affecting {alpha}1-antichymotrypsin and interleukin-1 plasma levels increases Alzheimer’s disease risk. Ann. Neurol., 48: 388-391, 2000.[Medline]
  19. Hulkkonen J., Laippala P., Hurne M. A rare allele combination of interleukin gene complex is associated with high interleukin-1 ß plasma levels in healthy individuals. Eur. Cytokine Network, 11: 251-255, 2000.[Medline]
  20. Apte R., Voronov E. Interleukin 1: a major pleotropic cytokine in tumor-host interactions. Semin. Cancer Biol., 12: 277-290, 2002.[Medline]
  21. Marth C., Zeimet A. G., Herold M., Brumm C., Windbichler G., Muller-Holzner E., Offner F., Feichtinger H., Zwierzina H., Daxenbichler G. Different effects of interferons, interleukin-1 ß and tumor necrosis factor-{alpha} in normal (OSE) and malignant human ovarian epithelial cells. Int. J. Cancer, 67: 826-830, 1996.[Medline]
  22. Chen Z., Fadiel A., Feng Y., Ohtani K., Rutherford T., Naftolin F. Ovarian epithelial carcinoma tyrosine phosphorylation, cell proliferation, and ezrin translocation are stimulated by interleukin 1{alpha} and epidermal growth factor. Cancer (Phila.), 92: 3068-3075, 2001.
  23. El-Omar E. M., Carrington M., Chow W. H., McColl K. E., Bream J. H., Young H. A., Herrera J., Lissowska J., Yuan C. C., Rothman N., Lanyon G., Martin M., Fraumeni J. F., Jr., Rabkin C. S. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature (Lond.), 404: 398-402, 2000.[Medline]
  24. Sehouli J., Mustea A. Interleukin-1 receptor antagonist gene polymorphism and cancer. Clin. Infect. Dis., 34: 1535-1536, 2002.[Medline]
  25. Sehouli J., Mustea A., Konsgen D., Katsares I., Lichtenegger W. Polymorphism of IL-1 receptor antagonist gene: role in cancer. Anticancer Res., 22: 3421-3424, 2002.[Medline]
  26. Barber M. D., Powell J. J., Lynch S. F., Fearon K. C., Ross J. A. A polymorphism of the interleukin-1 ß gene influences survival in pancreatic cancer. Br. J. Cancer, 83: 1443-1447, 2000.[Medline]
  27. Sehouli J., Lichtenegger W., Hauptmann S., Dietel M. Therapie von Borderline-Tumoren des Ovars. Frauenarzt, 43: 1202-1207, 2002.
  28. Tarlow J. K., Blakemore A. F., Lennard A., Solari R., Hughes H. N., Steinkasserer A., Duff G. W. Polymorphism in human IL-1 receptor antagonist gene intron 2 is caused by variable numbers of an 86-bp tandem repeat. Hum. Genet., 91: 403-404, 1993.[Medline]
  29. Irvine K. R., Rao J. B., Rosenberg S. A., Restifo N. P. Cytokine enhancement of DNA immunization leads to effective treatment of established pulmonary metastases. J. Immunol., 156: 238-245, 1996.[Abstract]
  30. Corbacioglu S., Pietsch T., Koenig A., Welte K. Interleukin-1 receptor antagonist: a powerful inhibitor of tumor vascularization and tumor growth in vivo. Sixth International Symposium on Pediatric Neuro-Oncology, 35 M. D. Anderson Cancer Center Houston, TX 1994.
  31. Arend W. P. Interleukin-1 receptor antagonist. A new member of the interleukin family. J. Clin. Investig., 88: 1445-1451, 1991.
  32. Dinarello C. A. The interleukin-1 family: 10 years of discovery. FASEB J., 8: 1314-1325, 1994.[Abstract]
  33. Vamvakopoulos J., Green C., Metcalfe S. Genetic control of IL-1ß bioactivity through differential regulation of the IL-1 receptor antagonist. Eur. J. Immunol., 32: 2988-2996, 2002.[Medline]
  34. Arend W. P., Malyak M., Guthridge C. J., Gabay C. Interleukin-1 receptor antagonist: role in biology. Annu. Rev. Immunol., 16: 27-55, 1998.[Medline]
  35. Unfried G., Tempfer C., Schneeberger C., Widmar B., Nagele F., Huber J. C. Interleukin 1 receptor antagonist polymorphism in women with idiopathic recurrent miscarriage. Fertil. Steril., 75: 683-687, 2001.[Medline]
  36. Machado J. C., Pharoah P., Sousa S., Carvalho R., Oliveira C., Figueiredo C., Amorim A., Seruca R., Caldas C., Carneiro F., Sobrinho-Simoes M. Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma. Gastroenterology, 121: 823-829, 2001.[Medline]
  37. Mustea A., Sehouli J., Konsgen D., Stengel D., Sofroni D., Lichtenegger W. Interleukin 1 receptor antagonist (IL-1RA) polymorphism in women with cervical cancer. Anticancer Res., 23: 1099-1102, 2003.[Medline]
  38. Hefler L., Ludwig E., Lebrecht A., Zeillinger R., Tong-Cacsire D., Koelbl H., Leodolter S., Tempfer C. B. Polymorphism of the interleukin-1 gene cluster and ovarian cancer. J. Soc. Gynecol. Investig., 9: 386-390, 2002.[Medline]
  39. Dent J., Hall G. D., Wilkinson N., Perren T. J., Richmond I., Markham A. F., Murphy H., Bell S. M. Cytogenic alterations in ovarian clear cell carcinoma detect by comparative genomic hybridisation. Br. J. Cancer, 88: 1578-1583, 2003.[Medline]
  40. Levine D. A., Boyd J. The androgen receptor and genetic susceptibility to ovarian cancer: results from a case series. Cancer Res., 61: 908-911, 2001.[Abstract/Free Full Text]
  41. Gershoni-Baruch R., Dagan E., Israeli D., Kasinetz L., Kadouri E., Friedman E. Association of the C677T polymorphism in the MTHFR gene with breast and/ or ovarian cancer risk in Jewish women. Eur. J. Cancer, 36: 2313-2316, 2000.




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sehouli, J.
Right arrow Articles by Lichtenegger, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sehouli, J.
Right arrow Articles by Lichtenegger, W.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Cell Growth & Differentiation