Abstract & Introduction

The etiology of ovarian cancer is largely unknown.

One hypothesis is that the inefficient removal of the blood clots and fibrin products which are deposited in the vicinity of the ovary by retrograde menstruation might be associated with an increased risk of ovarian cancer.

Several single nucleotide polymorphisms within genes which comprise the fibrinolytic system have been shown to have functional effects on the rate of blood clot degradation.

These were considered to be candidate genes in the present study.

Aim

We studied the genotype distributions of 12 functional SNPs of four genes (tPA, uPA PAI1 and TAFI) among 775 ovarian cancer cases and 889 controls.

Results

No significant associations were seen between any of the ten SNPs and the risk of ovarian cancer as a whole, or in any histologic subgroup.

Discussion

Germline known functional variants of genes in the fibrinolytic system are not associated with risk of ovarian cancer.

Although the cause of ovarian cancer is unknown, various risk factors appear to be related to reproduction, contraception and inflammation.

Parity, breast-feeding, oral contraceptives and tubal ligation are all protective. In contrast, endometriosis and talc are among the few known risk factors.

On the whole, these observations suggest that factors which diminish the number of ovulatory cycles are protective and factors that increase local inflammation may be carcinogenic.

Endometriosis is associated with a significantly increased risk of ovarian cancer [1], [2].

The prevalence of endometriosis in patients with epithelial ovarian cancer is 36% for clear cell carcinoma and 19% for endometrioid ovarian carcinoma.

In one study, ovarian cancer was found in 5–10% of ovarian endometriotic lesions [3]. It is believed that retrograde menstruation is necessary for the development of endometriosis [4].

Tubal ligation and oral contraceptives prevent (or reduce) retrograde menstruation and both are associated with a reduction in the risk of ovarian cancser [5]–[8].

Despite the high prevalence of retrograde menstruation in up to 90% of women [9], [10], the prevalence of endometriosis is estimated to be in the range of 7–10% of women of reproductive age.

One speculative explanation for this discrepancy is that an intact fibrinolytic process clears blood clots and endometrial cells from pelvic structures.

We hypothesise that women with a defective fibrinolysis system may not remove blood clots effeciently and, as a result, this increases the time that endometrial cells in menstrual blood clots remain in contact with pelvic structures.

These cells might possibly implant on the peritoneal or ovarian surface[11]. If this hypothesis is correct, there may be an association between defective fibrinolysis and the risk of ovarian cancer.

The fibrinolytic system comprises a family of proteins that includes two plasminogen activators (urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA)), the zymogen plasminogen, the active form plasmin, and inhibitor proteins like plasminogen activator inhibitor type 1 (PAI1) and thrombin-activated fibrinolysis inhibitor (TAFI).

The tPA is the primary mediator of local intravascular fibrinolysis. Genetic factors play a role in the variation of endothelial t-PA release [12].

The c.−7351C>T variant (rs2020918) within the enhancer region of the t-PA gene is strongly correlated with endothelial t-PA release rates. This SNP is associated with an increased risk of myocardial infarction [13].

Elevated levels of uPA promote tumor cell spread and metastasis and are associated with relatively poor prognosis [14].

A functional polymorphism of the uPA gene has been described. This is a substitution of C to T in the nucleotide sequence of exon 6 encoding the kringle domain resulting in Pro to Leu replacement at codon 141 (rs2227564).

PAI1 is a serine protease inhibitor that binds to both plasminogen activators, t-PA and u-PA, forming a stable complex that is cleared from the circulation by hepatic cells [15].

High levels of PAI1 are a common finding in ovarian cancer [16]. PAI1 over-expression is also associated with poor survival in ovarian cancer patients [17]–[19].

Furthermore, it has been suggested that PAI1 levels are important in the prognosis of breast and cervical cancers [20]–[22].

In cancer transplantation models, tumor growth, invasion, and angiogenesis are diminished in PAI1- deficient mice [23], [24].

Several single nucleotide polymorphisms (SNPs) in the PAI1 gene have been associated with a significant increase in PAI1 protein expression [25].

Thrombin-activated fibrinolysis inhibitor (TAFI) is a potent inhibitor of fibrinolysis that removes carboxy terminal–lysine residues from partially-degraded fibrin and decreases plasminogen binding [26].

In vivo animal studies demonstrate that inhibition of TAFI activity by carboxypeptidase increases thrombolysis [27].

Circulating levels of TAFI are strongly controlled by six polymorphic variations in the promoter and the 3'UTR region of the TAFI gene [28].

We propose that functional variants in these genes may be related to ovarian cancer risk. The objective of the present study was to determine if any of known functional polymorphisms of these four genes of the fibrinolytic system are associated with an increased risk of invasive ovarian cancer.

PLoS ONE. 2009; 4(6): e5918.

Published online 2009 June 15.

doi: 10.1371/journal.pone.0005918.

Yaakov Bentov,^1,2* Theodore J. Brown,^1,2 Mohammad R. Akbari,³ Robert Royer,³ Harvey Risch,⁴ Barry Rosen,^1,5 John McLaughlin,⁵ Ping Sun,³ Shiyu Zhang,³ Steven A. Narod,³ and Robert F. Casper^1,2

¹Department of Obstetrics and Gynecology, University of Toronto, Toronto, Canada ²Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada ³Women's College Research Institute, Women's College Hospital, University of Toronto, Toronto, Canada ⁴Yale University, New Haven, Connecticut, United States of America ⁵Gynecologic Oncology, Princess Margaret Hospital, Toronto, Canada Sudhansu Kumar Dey, Editor Cincinnati Children's Research Foundation, United States of America

*E-mail: Bentov@lunenfeld.ca Conceived and designed the experiments: YB TB BR JM SAN RC. Performed the experiments: RR PS SZ. Analyzed the data: YB RR HR JM SAN RC. Wrote the paper: YB TB MRA SAN RC. Received March 17, 2009; Accepted May 19, 2009.

SEE FULLTEXT

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2691597&tool=pmcentrez

http://www.e-medicum.com/noticiasDelDia/verNoticia.php?noticia=82914