Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer

doi:10.1016/S0009-9120(00)00048-5

Clinical Biochemistry

Volume 33, Issue 3, April 2000, Pages 197-202

https://doi.org/10.1016/S0009-9120(00)00048-5 Get rights and content

Abstract

Objectives: We have investigated the AAG and its genetic variants concentrations in plasma samples of 61 patients suffering from different types of cancers.

Design and methods: The patients were shared out in three groups, breast, lung, and ovary cancers groups. AAG concentration was measured by an immunonephelometric method and the phenotype was determined, after desialylation of plasma by analytical isoelectric focusing. Detection of AAG variants was made by immunoblotting and their proportions were determined by laser densitometry analysis. A population of 74 healthy individuals served as controls.

Results: The plasma concentrations of AAG in the breast and lung cancer groups were 2.5 times increased, while in the ovary cancer group, the concentrations were 1.6 times increased. AAG concentrations in the cancer population ranged between 0.45 and 2.85 g/L (mean value 1.12 ± 0.51 g/L). The proportions of the ORM1 and ORM2 variants were similar to those in the healthy population. In breast and lung cancer groups, the relative concentrations of genetic variants were increased more than 2.5 fold, whereas a 1.6-fold increase was observed in the ovary cancer group.

Conclusions: These results show that AAG plasma concentrations are increased in these types of cancers and that changes in the expression of the genetic variants of AAG could also occur according to the type of cancer.

Introduction

A lpha-1-acid glycoprotein (AAG or orosomucoid) is a plasma glycoprotein with a high proportion of glycosylated components. For healthy people, plasma levels of AAG are reported to range between 0.4 and 1.1 g/L 1, 2. AAG exhibits a genetic polymorphism in the desialylated state (3). The AAG synthesis is controlled by various alleles at two loci (4). The first locus (ORM1) encoded two main variants (ORM1 F1 and ORM1 S), while the second locus (ORM2) is mainly monomorphic (ORM2 A variant). In the general population, three phenotypes are most frequently observed for AAG, ORM1 F1S/ORM2 A, ORM1 F1/ORM2 A, and ORM1 S/ORM2 A, depending on the presence of two or three of these variants in plasma. The relative proportions of the ORM1 and ORM2 variants vary according to the AAG phenotype, and also vary between individuals of the same phenotype (5). With IEF methods using carrier ampholytes or immobilized pH gradients and subsequent immunoblotting or immunoprinting with anti-human AAG antibodies, the various genetic variants of AAG in neuraminidase-treated plasma can be detected 4, 6, 7.

Two different genes coding for AAG in human genome have been cloned and sequenced (8) the AAG-A and the AAG-B/B′ genes. The AAG-A gene is structurally similar to the AAG-B/B′ gene, but contains 22 base substitutions. A study using transgenic mice has shown that the AAG-A gene encodes the variants ORM1 and the AAG-B/B′ gene, the variants ORM2 (9).

The plasma concentration of AAG increases up to 5 fold in various acute-phase responses, e.g., inflammation, stress, cancer, pregnancy, myocardial infarction, and neonatal infections (10). Additionally, the relative proportions of the gene products of the AAG-A and AAG-B/B′ genes (the variants ORM1 and ORM2, respectively) have been also found to change during acute-phase reactions 11, 12.

In this study, we have determined the relative proportions and concentrations of the AAG variants in plasma of 61 cancer patients, shared out in three groups, breast cancer, lung cancer, and ovarian cancer groups. The results were compared to those obtained in a population of 74 healthy subjects (13).

Section snippets

Subjects

Sixty-one patients including 39 breast cancer, 16 lung cancer, and 6 ovary cancer, took part in the study. All patients were treated by chemotherapy. Anticancer drugs according to diagnosis were cisplatin, endoxan, epirubicin, 5-fluorouracil, taxol, docetaxel, mitomycin C, doxorubicin, etoposide, alone or in association. Blood was obtained by venipuncture and collected into glass tubes containing lithium heparinate. Heparinized blood samples were centrifuged at 600 g for 20 min, at 4°C and the

Demographic and clinical data of the cancer patients

The demographics and the clinical data of the cancer patients included in the study are shown in Table 1.

AAG and AAG variants concentrations in plasma of cancer patients

The AAG concentrations (mean ± SD) measured in the three groups of cancer patients and in the control group are listed in Table 2. The plasma AAG concentrations were significantly increased (p < 0.0001) in the cancer patients (1.12 ± 0.51 g/L) as compared to the control group (0.50 ± 0.14 g/L). After AAG was phenotyped in the desialylated plasma, there were 34 patients with the ORM1

Discussion

The results of this study show that the mean plasma AAG concentrations in breast, lung, and ovary cancers were increased two times higher than that in the healthy population. The breast or lung cancer groups also showed a 2-fold increase in AAG concentration whereas in the ovary cancer group, AAG concentration was only 1.6 times increased. In the ovary cancer group, the AAG induction should be weaker than in the other cancer groups.

The observed AAG phenotypes in this cancer population were the

Acknowledgements

This work was supported by grants from the French Medicine Agency (Project: Rôle de l’hétérogénéité de l’alpha-1-glycoprotéine acide dans la variabilité interindividuelle de réponse aux médicaments) and le Ministère de l’Education Nationale EA 427.

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ClinicalExpression of the genetic variants of human alpha-1-acid glycoprotein in cancer

Abstract

Introduction

Section snippets

Subjects

Demographic and clinical data of the cancer patients

AAG and AAG variants concentrations in plasma of cancer patients

Discussion

Acknowledgements

Plasma proteins

J Chromatogr

J Chromatogr

Drug binding to human alpha-1-acid glycoprotein in health and disease

Pharmacol Rev

Clinical relevance of alpha-1-acid glycoprotein in health and disease

Human plasma alpha-1-acid glycoproteinBiochemical properties, the amino acid sequence and the structure of the carbohydrate moiety, variants and polymorphism

Orosomucoid system17 additional orosomucoid variants and proposal for a new nomenclature

Vox Sang

Binding of d-methadone, l-methadone and dl-methadone to proteins in plasma of healthy volunteersRole of the variants of alpha-1-acid glycoprotein

Clin Pharmacol Ther

Three new orosomucoid (ORM) variants revealed by isoelectric focusing and print immunofixation

Hum Genet

Clinical
Expression of the genetic variants of human alpha-1-acid glycoprotein in cancer