MUC1 568 A/G genotype-dependent Cancer Antigen 15-3 levels in breast cancer patients
Introduction
Cancer Antigen 15-3 (CA 15-3) is a mucin, namely MUC1, which is widely used as a tumor marker for monitoring treatment and recurrence of invasive breast cancer [1], [2], [3]. Although CA 15-3 is useful in the setting of disease follow-up, its diagnostic merit is questionable [4], [5], [6].
In this era we are able to investigate less obvious variables than gender and age that have a significant effect on disease marker levels. A contemporary example is the influence of single nucleotide polymorphisms (SNPs) on the accuracy of markers in various diseases [7], [8].
Recently, we reported an association between the 568 A/G polymorphism in the mucine-encoding gene (MUC1) and variation of serum levels of KL-6, a promising marker for interstitial lung diseases [7], [9], [10]. KL-6 refers to the same mucin as CA 15-3 does, but instead uses an antibody directed against a different epitope. The observation that the SNP accounted for a significant portion of the variation of circulating KL-6 serum levels in individuals prompted us to investigate whether serum levels of CA 15-3 are equally affected by the 568 A/G polymorphism in healthy women and women with breast cancer.
Our secondary objective was to test whether the − 568 A/G polymorphism might contribute to the propensity to develop breast cancer. To test this hypothesis, the genotype frequency distributions were compared between healthy women and women with either benign or malignant breast tumors.
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Study group
The medical ethical committees of both participating hospitals approved the study conducted and all subjects gave formal written consent.
Between 2005 and 2008, venous blood samples were collected from 230 unrelated women who presented at the outpatient clinic of the Daniel den Hoed Cancer Center in Rotterdam for the first time. The mean ± SD age at presentation was 54.3 ± 12.1 years. No prior tumor resection or other forms of oncologic intervention had been performed. Sixty-seven women had
Results
The results of the influence of the MUC1 568 A/G polymorphism on serum CA 15-3 levels in healthy women are detailed in Table 1. Smoking history or age did not significantly influence CA 15-3 levels in a multivariate analysis (data not shown). The control group was in Hardy–Weinberg equilibrium for MUC1 568 A/G polymorphism (p > 0.1). However, the patient group as a whole was not (p < 0.008). When this group was divided into subgroups based on the type of tumor, i.e. benign, malignant and ductal
Discussion
This study shows that the MUC1 568 A/G polymorphism is of strong influence on serum CA 15-3 levels in healthy women, and those with benign breast disease or breast cancer.
Even though it is not endorsed by the American Society of Clinical Oncology [12], CA 15-3 is widely used as a follow-up marker in breast cancer patients [6]. Further, CA 15-3 is highly discouraged as a diagnostic marker on account of its poor sensitivity. Yet preoperative CA 15-3 levels greater than 30 U/mL have been shown to
Acknowledgments
The authors wish to thank Mariska Crans, Karel van Huffelen, Netty van Trooyen, Nettie Bosch, Jan Broess, Natalie Pot, Ada Van Eekelen, and Joke Paardekoper for their technical and logistic assistance. Also greatly acknowledged is Roche Diagnostics BV, the Netherlands for providing complimentary CA 15-3 reagent kits.
References (22)
- et al.
Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease
Eur. J. Cancer
(1994) - et al.
ACE I/D-corrected Z-scores to identify normal and elevated ACE activity in sarcoidosis
Respir. Med.
(2007) - et al.
Episialin, a carcinoma-associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini
J. Biol. Chem.
(1990) - et al.
Prognostic significance of MUC1 epithelial mucin expression in breast cancer
Hum. Pathol.
(1995) - et al.
Comparison of CEA, MCA, CA 15-3 and CA 27-29 in follow-up and monitoring therapeutic response in breast cancer patients
Anticancer Res.
(1999) - et al.
C-erbB-2, CEA and CA 15.3 serum levels in the early diagnosis of recurrence of breast cancer patients
Anticancer Res.
(1999) - et al.
2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology
J. Clin. Oncol.
(2001) Clinical practice guidelines for the use of tumor markers in breast and colorectal cancer. Adopted on May 17, 1996 by the American Society of Clinical Oncology
J. Clin. Oncol.
(1996)Serum tumor markers in breast cancer: are they of clinical value?
Clin. Chem.
(2006)- et al.
The mucin-1 568 adenosine to guanine polymorphism influences serum Krebs von den Lungen-6 levels
Am. J. Respir. Cell Mol. Biol.
(2006)
Detection of soluble tumor-associated antigens in sera and effusions using novel monoclonal antibodies, KL-3 and KL-6, against lung adenocarcinoma
Jpn. J. Clin. Oncol.
Cited by (4)
Mucins in the pathogenesis of breast cancer: Implications in diagnosis, prognosis and therapy
2011, Biochimica et Biophysica Acta - Reviews on CancerCitation Excerpt :The levels of CA15.3 (MUC1) also appear to be significantly influenced by the presence of one or more single nucleotide polymorphisms (SNPs) in the MUC1 gene. In a study among Dutch women to investigate the effect of the 568 A/G polymorphism in MUC1 on serum CA15.3 levels, it was observed that women who had the GG genotype (21% of healthy, 24% of benign breast disease and 27% of BC patients) had significantly higher levels of serum CA15.3 compared to those with the AG or AA genotype [67]. These differences were attributed to the variable number of tandem repeats, with patients having the GG genotype having a larger number of repeats (and hence a higher expression of MUC1) than those with other genotypes.
Genotype-dependent values of serum biomarkers in interstitial lung diseases
2012, Nederlands Tijdschrift voor Klinische Chemie en Laboratoriumgeneeskunde