Mannose-binding lectin codon 54 genetic polymorphism and vaginal protein levels in women with gynecologic malignancies

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Abstract

Objectives

Mannose-binding lectin (MBL), an innate immune system component that binds to carbohydrates, activates the complement cascade and promotes destruction of microorganisms and abnormal cells. We determined whether a polymorphism in the MBL gene influences vaginal MBL protein concentrations and the occurrence of gynecologic malignancies.

Study design

DNA from 289 women seen in a gynecologic oncology practice and from 126 healthy women was tested for an MBL codon 54 single nucleotide polymorphism by polymerase chain reaction and endonuclease digestion. Vaginal supernatants from 282 of these women were assayed for MBL protein by ELISA.

Results

The normal (A,A) genotype was present in 84.1% of 126 healthy women and 85.3% of 95 women with a benign diagnosis as opposed to 70.0% of 70 women with ovarian cancer (p = 0.02). The MBL variant allele (allele B) frequency was 8.7% in healthy women, 8.4% in women with a benign diagnosis and 17.1% in women with ovarian cancer (p = 0.02). Vaginal MBL protein concentrations were highest in women with the A,A genotype, intermediate in A,B heterozygotes (p < 0.0001) and lowest in B,B homozygotes (p = .0097).

Conclusion

The MBL 54 polymorphism and reduction in vaginal MBL concentrations may be a risk factor for development of epithelial ovarian cancer.

Introduction

Mannose-binding lectin (MBL) is a homo-oligomeric protein composed of 3 to 6 32 kDa subunits present in the circulation [1] and in body secretions, including the vagina [2]. It binds to carbohydrate residues on the surface of microorganisms and activates the complement cascade [3]. Microbial killing occurs by complement-mediated lysis and by the ingestion by phagocytic cells of microorganisms bearing complement components or MBL on their surface.

The gene coding for MBL, gene symbol mbl2, on chromosome 10q11,2-q21 [4] has three functional single nucleotide polymorphisms in exon 1, with the polymorphism at codon 54 being the most common in Caucasian populations [2]. The substitution of adenosine for guanine at codon 54 leads to the insertion of aspartic acid instead of glycine in the MBL protein. This change results in inhibition of oligomerization of the MBL subunits and impairs the stability and functional activity of the protein [5]. As a consequence, circulating and vaginal MBL concentrations are greatly lowered and MBL-mediated complement activation is reduced in individuals carrying one or two copies of the codon 54 polymorphism [2], [6]. The polymorphic variant at codon 54 is commonly identified as allele B, to differentiate it from the wild type allele, allele A. Codon 54 allele B is the most common cause of low MBL concentrations in the European population [7].

Oligosaccharides on the surface of mammalian cells normally terminate with sialic acid residues and therefore do not react with MBL. MBL, however, has been shown to bind to altered oligosaccharides expressed on cells undergoing apoptosis or necrosis [8] as well as on the surface of virus-infected [9] or malignantly transformed [10], [11] cells. MBL binding to altered oligosaccharides exposed on the surfaces of tumor cells has been shown to induce tumor cell destruction [10].

The objective of the present study was to determine the prevalence of the MBL 54 polymorphism, as well as vaginal MBL protein levels, in women presenting to an academic gynecologic oncology practice. Our hypothesis was that possession of the variant B allele would be associated with decreased vaginal MBL levels, and therefore retard the immune response to malignantly transformed cells in the female genital tract.

Section snippets

Materials and methods

Vaginal swabs were collected from 289 women presenting to an academic gynecologic oncology practice. Healthy controls (126) of similar ages and ethnicity were selected from women being seen for a routine check-up who had a normal Pap smear and no clinical indication of disease. They did not undergo a pelvic ultrasound examination. IRB approval and written informed consent were obtained from each participant. Human experimentation was performed in accordance with The Code of Ethics of the

Results

The most common diagnosis in our subject population was a benign condition (n = 95), followed by endometrial cancer (n = 88) and ovarian cancer (n = 70). Cervical cancer was diagnosed in 27 women while nine had other malignancies (Fallopian tube cancer, labial cancer, sarcoma, vaginal or vulva cancer). The benign conditions were 45.8% abnormal Pap readings (ASC-US or low grade cervical dysplasia), 15.0% ovarian cysts, 15.0% uterine fibroids, 7.8% cervical dysplasia, 6.8% post-menstrual bleeding, 3.9%

Comment

Women diagnosed with ovarian cancer had a reduced prevalence of the normal MBL codon 54 A,A genotype and an increased occurrence of the polymorphic allele B variant in comparison to healthy women and those with benign conditions. This was especially the case in women diagnosed as having epithelial ovarian cancer. These findings parallel a previous investigation that demonstrated a reduced occurrence of the MBL A,A genotype in Polish women with ovarian cancer compared to healthy controls [12].

Condensation

A polymorphism in the MBL2 gene that leads to a reduction in vaginal mannose-binding protein concentration may be a risk factor for epithelial ovarian cancer.

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