Rapid CommunicationCHEK2 variants predispose to benign, borderline and low-grade invasive ovarian tumors
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)
- et al.
Mutations in CHEK2 associated with prostate cancer risk
Am. J. Hum. Genet.
(2003) - et al.
CHEK2 is a multiorgan cancer susceptibility gene
Am. J. Hum. Genet.
(2004) - et al.
BRCA1 and BRCA2 mutation analysis of 208 Ashkenazi Jewish women with ovarian cancer
Am. J. Hum. Genet.
(2000) - et al.
Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer
Am. J. Hum. Genet.
(2001) - et al.
Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer
Gynecol. Oncol.
(2005) - et al.
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase
Science
(1998)
Cited by (52)
Current and emerging biomarkers in ovarian cancer diagnosis; CA125 and beyond
2023, Advances in Protein Chemistry and Structural BiologyCitation Excerpt :The CHEK2 mutations are also known to play a role in OC carcinogenesis. The CHEK2 gene encodes a protein kinase that is activated by DNA damage and is also reported to interact with BRCA1, promoting cell survival after DNA damage (Baysal et al., 2004; Szymanska-Pasternak et al., 2006). Reportedly, OCs can be classified into histological subtypes with different risk factors and clinical features.
Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D
2022, BreastCitation Excerpt :The correlation between melanoma and CHEK2 PVs is under investigation [55]. A Polish report suggests an association between a missense mutation in the CHEK2 gene (I157T) and benign, borderline and low-grade malignant ovarian tumours [56]. Some meta-analyses reported a modestly increased CRC-correlated risk with variant 1100delC and I157T, particularly in patients older than 50 years, which may increase with a positive CRC FH [57,58].
Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance
2022, European Journal of Medical GeneticsCitation Excerpt :Regarding the variant c.470T > C, it was found in a patient diagnosed with undifferentiated OC at the age of 41. A study by Szymanska-Pasternak et al. associated this variant with an increased risk of borderline OC, with low-grade invasive cancers and cystadenomas, but not with ovarian cancer of high grade (Szymanska-Pasternak et al., 2006). However, other studies performed in CHEK2 carriers did not show an increased risk of OC (Daly et al., 2019).
Recurrent Acromegaly in a Patient With a CHEK2 Mutation
2022, AACE Clinical Case ReportsCitation Excerpt :Three truncating mutations (1100delC, IVS2 + 1G> A, and del5395) and one missense mutation (I157T) of the CHEK2 gene have been associated with an increased risk of papillary thyroid cancer.7 The CHEK2 I157T mutation has also been linked to endometrial cancer8 and benign and low-grade malignant ovarian tumors.9 Alterations in CHEK2 expression have been reported in pituitary adenomas.10
- 1
Both authors contributed equally to this work.