Original contributionInvolvement of pelvic inflammation–related mismatch repair abnormalities and microsatellite instability in the malignant transformation of ovarian endometriosis☆
Introduction
Endometriosis is a common gynecological disease affecting approximately 10% of women of reproductive age [1]. Since Sampson [2] first suggested that ovarian cancer can arise from endometriosis in 1925, clinical analyses have shown the coexistence of endometriosis and epithelial ovarian cancer, particularly endometrioid adenocarcinoma (EAC) and clear cell carcinoma (CCC) [3], [4], [5], [6]. Recently, endometriosis has been reported to be associated with an increased risk of epithelial ovarian cancer, especially CCCs and EACs [3], [6], [7]. Endometriotic lesions trigger a local inflammatory reaction involving the activation of macrophages and cytokine release [8], and serum cytokine levels have been reported to be associated with the stage of endometriosis [9]. Inflammation in the ovary, including ovulation and pelvic inflammatory disease, has been proposed to play a role in the pathogenesis of ovarian cancer [10], [11]. These reports suggest that inflammation is involved in the carcinogenesis of ovarian cancer arising from endometriosis.
A variety of molecular events, such as p53 alterations [12], [13], PI3K (phosphoinositide-3 kinase) amplification [14], PTEN[15], [16] and K-ras mutations [17], and HNF-1β (hepatocyte nuclear factor-1 beta) amplification [18] is found in endometriosis. A recent study provided evidence of ARID1A (AT-rich interactive domein-containing protein 1A) mutation in endometriosis-associated ovarian carcinomas [19]. However, the precise molecular mechanisms of ovarian cancer arising from endometriosis are still to be elucidated. Endometriosis is characterized by the presence of endometrial tissue including endometrial epithelial cells outside the uterus. The morphological and endocrinologic characteristics of endometriosis-derived ovarian tumors suggest that the carcinogenic process responsible for the malignant transformation of endometriosis to ovarian cancer shares similarities with the carcinogenesis of endometrial carcinoma. Impaired mismatch repair (MMR) is reportedly crucial for the early stages of endometrial carcinogenesis, in which defective MMR genes, such as hMLH1 and hMSH2, induce a high frequency of replication errors as microsatellite instability (MSI) and, hence, promote tumorigenesis [20], [21]. However, the significance of MMR abnormalities in the malignant transformation of endometriosis has not been fully determined.
Therefore, in this study, the immunohistochemical expression of MMR proteins (hMLH1 and hMSH2), MSI, and mutations in the mononucleotide repeats of 5 genes (TGF-βRII [transforming growth factor beta receptor type II], PTEN, BAX [bcl-2 associated X], hMSH6 [human mutS homolog 6], and HNF-1β) were investigated in endometriosis, ovarian carcinoma accompanied by endometriosis (OCEM), and solitary ovarian carcinoma. The relationship between MSI and clinicopathologic parameters including inflammatory factors was analyzed.
Section snippets
Case selection and DNA preparation
Twenty-seven cases of ovarian endometriosis, 25 cases of OCEM, 14 cases of CCC, 12 cases of EAC, and 13 cases of high-grade serous adenocarcinoma were selected from the pathology file of Shinshu University Hospital. None of the patients had a family history of breast or ovarian cancer. All patients visited the Shinshu University Hospital between 1996 and 2008 and underwent surgery. Their tissue specimens were reviewed to confirm the histopathologic diagnosis using the standard criteria [22].
Expression of hMLH1 and hMSH2 in endometriosis
Representative immunostaining profiles for hMLH1, hMSH2, and Ki-67 are shown in Fig. 1. hMLH1 and hMSH2 staining was observed in both the cytoplasm and nucleus. We evaluated nuclear staining using a PI. All control slides yielded negative staining. The PI for hMLH1, hMSH2, and Ki-67 in normal endometrial tissue (eutopic endometria) and endometriotic tissue (ectopic endometria) is described as the mean ± SD in Fig. 2A and Table 1.
In the eutopic endometrial epithelia, the expression levels of
Discussion
In the present study, the immunohistochemical expression of hMLH1 and hMSH2 was found to decrease in the following order: ovarian endometriosis > OCEM > solitary ovarian carcinoma. Our study also demonstrated that the immunohistochemical expression levels of hMLH1 and hMSH2 in ectopic endometria were significantly decreased compared with those in eutopic endometria. The expression of hMLH1 and hMSH2 was observed in normal endometria, which is consistent with previous reports [21], [23]. The PI
Supplementary data
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