Abstract
DNA damage commonly occurs in cancer cells as a result of endogenous and tumor microenvironmental stress. In this study, we applied immunohistochemistry to study the expression of phosphorylated Chk2 (pChk2), a surrogate marker of the DNA damage response, in high grade and low grade of ovarian serous carcinoma. A phospho-specific antibody specific for threonine 68 of Chk2 was used for immunohistochemistry on a total of 292 ovarian carcinoma tissues including 250 high-grade and 42 low-grade serous carcinomas. Immunostaining intensity was correlated with clinicopathological features. We found that there was a significant correlation between pChk2 immunostaining intensity and percentage of pChk2 positive cells in tumors and demonstrated that high-grade serous carcinomas expressed an elevated level of pChk2 as compared to low-grade serous carcinomas. Normal ovarian, fallopian tube, ovarian cyst, and serous borderline tumors did not show detectable pChk2 immunoreactivity. There was no significant difference in pChk2 immunoreactivity between primary and recurrent high-grade serous carcinomas. In high-grade serous carcinomas, a significant correlation (P < 0.0001) in expression level (both in intensity and percentage) was found between pChk2 and Rsf-1 (HBXAP), a gene involved in chromatin remodeling that is amplified in high-grade serous carcinoma. Our results suggest that the DNA damage response is common in high-grade ovarian serous carcinomas, especially those with Rsf-1 overexpression, suggesting that Rsf-1 may be associated with DNA damage response in high-grade serous carcinomas.
Highlights
Ovarian carcinomas comprise a diverse group of neoplasms that demonstrate distinct clinicopathological features and unique molecular genetic aberrations with respect to different histologic subtypes [1, 2]
We address three main questions: whether there is a difference in the level of DNA damage response (DDR) between highgrade and low-grade serous carcinoma; whether recurrent high-grade serous carcinomas have an altered DDR as compared to their primaries; whether there is a significant correlation in the expression levels between phosphorylated check point kinase 2 (Chk2) (pChk2) and Rsf-1 (HBXAP), a gene that is frequently upregulated in highgrade serous carcinoma and participates in generating DNA damage
Comparing low-grade to high-grade carcinomas, we found that 66 (26.4%) of 250 high-grade serous carcinomas, including primary and recurrent tumors, showed intense pChk2 immunoreactivity (3+) while only 3 (7.1%) of 42 low-grade serous carcinomas had immunostaining scores of 3+
Summary
Ovarian carcinomas comprise a diverse group of neoplasms that demonstrate distinct clinicopathological features and unique molecular genetic aberrations with respect to different histologic subtypes [1, 2]. Given the fact that different subtypes of ovarian tumors develop along distinct molecular pathways, we asked if the DNA damage response (DDR) is different among high-grade and low-grade serous carcinomas, the prototypes of type II and type I tumor, respectively. It has been well established that the DDR pathway is activated by endogenous and environmental cellular stress that is associated with DNA damage and has profound effects on determining cell fate. Given its critical role in tumor development, it has been proposed that harnessing the activity of DDR pathways may improve cancer treatment outcome after cytotoxic chemotherapy and irradiation therapy [7]. DDR is mediated by a signal transduction cascade involving the ataxia telangiectasia mutated (ATM-) check point kinase 2 (Chk2)-p53 axis
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