Original article
Angiotensin I–converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women

https://doi.org/10.1016/j.cancergencyto.2004.03.020Get rights and content

Abstract

Endometrial carcinoma is one of the most common gynecological malignancies. Most cases are diagnosed in older patients with diabetes, hypertension, or obesity. The renin-angiotensin system (RAS) has a central role controlling blood pressure and sodium homeostasis. RAS polymorphisms have been reported as genetic determinants of essential hypertension. The objective of this study was to analyze angiotensin I–converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women. The presence of an angiotensin converting enzyme (ACE) polymorphism was analyzed by polymerase chain reaction in DNA isolated from peripheral blood samples of 171 women: 70 cases with endometrial cancer (age, 63.6 ± 9.5 years) and 101 normal control women (age, 61.3 ± 6.4 years). We detected DD genotype in 47.5%, ID genotype in 44.3%, and II genotype in 8.2% of cases. The allele frequency was 0.69 for D allele and 0.30 for I allele. In normotensives, we found that the presence of I allele (genotypes ID and II) is significantly associated to an earlier age (56.0 ± 10.1 versus 65.8 ± 9.9) of onset of endometrial carcinoma (P = 0.029). We observed that normotensive women carriers of an allele I have a higher risk of development of endometrial cancer under the age of 63 years (odds ratio = 3.60, 95% confidence interval = 1.03–12.56; P = 0.037). Our findings suggest that ACE polymorphism may be associated with the development of endometrial carcinoma and with the onset of this tumor in younger women. The definition of a pharmacogenomic profile of human neoplasia may help to identify targets for the development of therapeutic or chemoprevention strategies.

Introduction

Endometrial carcinoma is one of the most common gynecological malignancies. The incidence has a trend to increase in most European countries and in the USA [1], [2], [3]. Obesity, hypertension, diabetes mellitus, and estrogen replacement therapy increase the risk of endometrial carcinoma [1], [2]. It occurs most frequently in women who are between 50 and 70 years of age [1], [2]. During the last decade there has been an increase in incidence in younger women. Detection of genetic alterations may be a useful tool to understand the etiology of endometrial cancer.

The activation of the renin-angiotensin system (RAS) plays an important role on the normal physiology and the progression of cardiac, renal, and other diseases [4], [5]. The angiotensin converting enzyme (ACE) inactivates vasodilator kinins and generates angiotensin II (Ang II) which is the major effector peptide of RAS system. The biological actions of Ang II are under mediation by at least two different receptor subtypes, Ang II receptor-subtype 1 (AT-1) and Ang II receptor-subtype 2 (AT-2) [4]. The most well-known physiological actions of angiotensin II, such as vasoconstriction, facilitation of sympathetic transmission, stimulation of aldosterone release, and promotion of cellular growth, are all mediated by the AT-1 receptor [4], [5]. AT-1 receptors are primarily found in the brain, adrenals, heart, vasculature and kidney. The AT-2 receptor is clearly distinct from the AT-1 receptor in tissue-specific expression, signaling mechanisms and diversity in molecular weight [4], [5]. Recent studies suggest that the AT-2 receptor may play a role in mediating anti-proliferation, cellular differentiation, apoptosis, and vasodilatation [4], [5]. The AT-2 receptor is highly expressed during fetal development, but rapidly declines at birth. Furthermore, the AT-2 receptor is highly abundant in the human uterus [4], [5].

The pathophysiological role of ACE in the endometrium is not fully understood. It has been suggested that the RAS is involved in the regulation of cell proliferation in the endometrium [4], [5], [6], [7], [8], [9]. The ACE gene (encoding kinases II, EC 3.4.15.1) is located on 17q23 and contains a polymorphism based on the presence (insertion: I allele) or absence (deletion: D allele) within an intron of a 287 bp nonsense DNA domain, resulting in genotypes II, ID and DD [10], [11], [12], [13]. Homozygotes for the I allele (genotype II) can display as low as half of the plasma ACE level compared with the homozygotes for the D allele (DD genotype), whereas the ID heterozygotes display an intermediate level [13]. Recently, it has been reported that ACE polymorphisms may be determinants in the development of human cancer [14], [15], [16], [17]. Furthermore, it has been suggested that long-term use of ACE may protect against cancer [18], and captopril, an ACE inhibitor, has been shown to inhibit proliferation of tumor cells and to reduce tumor growth [19], [20], [21], [22]. The implications of ACE polymorphisms on endometrial cancer remain to be established. Thus, the purpose of the present study is to characterize the distribution of ACE genotypes in endometrial cancer patients and to report its association with clinico-pathologic factors, in comparison with a normal control population of women without cancer.

Section snippets

Patients

We conducted a case-control study with the comparison of the frequencies of genotypes of ACE polymorphism of 171 eligible women: 70 cases with endometrial cancer (age, 63.6 ± 9.5 years) and 101 normal control women (age, 61.3 ± 6.4 years). The 70 cases with histologically confirmed endometrial cancer were admitted and treated at the Departments of Oncology and Gynecology, the Instituto Português de Oncologia, Porto, Portugal from 1998 to 2000. Clinical characteristics including histological

Results

We detected the DD genotype in 47.5%, the ID genotype in 44.3%, and the II genotype in 8.2% of cases. The allele frequency was 0.69 for D allele and 0.30 for I allele. DD genotype was detected in 21 hypertensive cases (H) and 8 normotensive cases (N); ID genotype was detected in 17 H cases and in 10 N cases; and II genotype was found in 2 H cases and 3 N cases. The association of ACE genotypes with the clinical features of endometrial cancer cases studied is shown in Table 1.

In normotensive

Discussion

Endometrial cancer is one of the most relevant female genital tract tumors both in incidence and mortality. The natural history of endometrial cancer is influenced by several risk factors such as obesity, hypertension, diabetes mellitus, and estrogen exposure [1], [2], [3].

The activation of the RAS has been suggested to play an important role on the normal physiology of many diseases, including hypertension and obesity. Furthermore, it has been suggested that steroid hormones may influence the

Acknowledgements

The authors thank Liga Portuguesa Contra o Cancro, Porto (Portuguese League Against Cancer) for their support. We gratefully acknowledge the funding of this work by the Ministry of Health of Portugal (CFICS- 226/2001).

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