Elsevier

Gynecologic Oncology

Volume 102, Issue 3, September 2006, Pages 429-431
Gynecologic Oncology

Rapid Communication
CHEK2 variants predispose to benign, borderline and low-grade invasive ovarian tumors

https://doi.org/10.1016/j.ygyno.2006.05.040Get rights and content

Abstract

Objective.

Three founder alleles of the CHEK2 gene have been associated with predisposition to a range of cancer types in Poland. Two founder alleles (1100delC and IVS2  +  1G  >  A) result in a truncated CHEK2 protein and the other is a missense substitution, leading to the replacement of a threonine with an isoleucine (I157T).

Methods.

To establish if these variants play a role in the etiology of ovarian tumors, we genotyped 1108 Polish women with various types of ovarian tumors and 4000 controls for the three CHEK2 variants. We included 539 Polish women with benign ovarian cystadenomas, 122 women with borderline ovarian malignancies and 447 women with invasive ovarian cancer.

Results.

Positive associations were seen with the CHEK2 I157T missense variant and ovarian cystadenomas (OR  =  1.7; P  =  0.005), with borderline ovarian cancers (OR  =  2.6; P  =  0.002) and with low-grade invasive cancers (OR  =  2.1; P  =  0.04). There was no association with ovarian cancer of high grade (OR  =  1.0). The association between the I157T missense variant was then confirmed in a second sample of Russian patients with borderline ovarian cancers (OR  =  2.7; P  =  0.06).

Conclusion.

These data indicate that CHEK2 variants may predispose to a range of ovarian tumor types of low malignant potential, but not to aggressive cancers.

Introduction

The CHEK2 gene encodes the human analogue of the yeast checkpoint kinases Cds1 and Rad53 [1]. Activation of CHEK2 in response to DNA damage prevents the cell from entering into mitosis. In Poland, there are three polymorphic variants of CHEK2, which, in aggregate, are present in 5.5% of the population; two of these (IVS2  +  1G   >  A and 1100delC) are rare and result in premature protein truncation [2]. The IVS2  +  1G   >  A appears to be characteristic founder mutation in the Polish population. The frequency of the 1100delC variant ranges from 0.2% to 1.4% in various European populations [3], [4] but this allele is infrequent in North America [5]. The 1100delC allele has been found to confer an elevated risk of breast cancer [3], [4] and prostate cancer [2], [6], [7]. The third variant is a common missense variant (I157T) that results in the substitution of an isoleucine for a threonine. We have recently reported that this variant is associated with increased risks of several cancer types in Poland [8] but these sites did not include ovarian cancer.

Ovarian cystadenoma is a benign tumor of the ovarian epithelium with histologic features similar to those of malignant cystadenocarcinoma. Both cystadenomas and carcinomas may be of serous or mucinous histology. We found that ovarian cystadenomas may be feature of the familial breast/ovarian cancer syndrome in Poland, after excluding families with BRCA1 mutations [9]. This observation prompted us to evaluate other candidate genes that may underlie the association between benign ovarian tumors and malignant breast tumors. Because CHEK2 has been associated with a wide range of cancer types in Poland, including breast cancer, it was selected for study.

Section snippets

Study subjects

Cases were collected from 32 hospitals in 5 provinces of Poland (Szczecin, Olsztyn, Gorzow, Kielce, Poznan) between 1997 and 2005. Patients were identified through the pathology departments of the participating hospitals. Study subjects were unselected for age and family history. Eligible patients were invited to participate in the study by attending an outpatient clinic where they signed informed consent and provided a blood sample. We included 539 Polish women with benign ovarian

Results

The frequencies of the CHEK2 missense variant I157T in Polish cases and controls are presented in Table 1, Table 2, Table 3. There was no overall association between this CHEK2 variant and invasive ovarian cancer in the data set (OR  =  1.2). However, we observed positive associations with the missense I157T variant and benign cystadenomas (OR  =  1.7; P  =  0.005) and with borderline lesions (OR  =  2.6; P  =  0.002). Because of the observed relationship between degree of invasiveness, we looked at the

Discussion

This report suggests an association between a founder missense mutation in the CHEK2 gene (I157T) and benign, borderline and low-grade malignant ovarian tumors. To our knowledge, this is the first identified example of a susceptibility gene for borderline ovarian tumors. The association was first seen among Polish women, but was confirmed in a second group of Russian patients. In contrast, the BRCA1 and BRCA2 genes predispose to invasive ovarian malignancies, but not to borderline malignancies

Acknowledgments

We would like to acknowledge the contributions of Menkiszak J, Rzepka-Gorska I, Kowalska E, Lener M, Matyjasik J, Stawicka M, Spaczynski M, Foszczynska-Kloda M, Czeszynska B, Czajka R, Fabian W, Raczynski A, Chosia M, Domagała W, Starczewski A, Niedzielski A, Lokociejewski J, Kaluzynski W, Abucewicz A, Sygut J, Starzewski J, Rudzinski R, Palys M, Witek A, Graniczka M, Mizgiert W, Pawlak L, Brych M, Klusewicz H, Rams L, Gromacki S, Gizewski A, Stefanowicz M, Frackowiak L, Malarkiewicz J,

References (12)

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Both authors contributed equally to this work.

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