Low Levels of DNA Damage Based on Phosphorylated CHK2 Immunoreactivity Support Ovarian Endometrioid and Clear Cell Carcinomas as Type I Tumors
MP Kshirsagar, W Jiang, RJ Kurman, I Shih. Johns Hopkins Medical Institutions, Baltimore, MD
Background: DNA damage can occur in cancer cells in response to a variety of endogenous and tumor microenvironment cues. Such damage may elicit or enhance genetic instability in tumor cells. DNA damage response appears to be more frequently detected in high grade serous carcinomas (prototypical Type II tumors) than in low grade serous carcinomas (prototypical Type I tumors) of the ovary (Jiang et al., abstract submitted to USCAP). It has been proposed that endometrioid and clear cell carcinomas of the ovary belong in the Type I category of ovarian tumors, based on their clinicopathologic features, and should therefore exhibit a low amount of DNA damage. We performed an immunohistochemical study using phosphorylated CHK2 (pCHK2) as the surrogate marker for DNA damage response to test this hypothesis.
Design: An antibody that reacts to phosphorylated CHK2 protein at the Threonine 68 residue was used for immunohistochemistry on paraffin sections from a total of 12 endometrioid carcinomas and 13 clear cell carcinomas. In addition, 28 low-grade serous carcinomas and 239 high-grade serous carcinomas of the ovary were tested, representing prototypical Type I and Type II tumors for comparison, respectively. pCHK2 immunoreactivity was semi-quantitatively scored by two pathologists independently using a five-tier grading system (0 to 4+).
Results: pCHK2 immunoreactivity was localized exclusively in the nuclei of tumor cells. Using an arbitrary cutoff (3+/4+ vs. 0/1+/2+), no endometrioid or clear cell carcinomas demonstrated intense immunoreactivity for pCHK2. Likewise, only 3 (10%) of 28 low grade serous tumors showed intense staining. When low grade serous, endometrioid and clear cell carcinomas are grouped as Type I tumors, only 3 (5.7%) of 53 Type I tumors (p = 0.012, chi-square test) demonstrated intense pCHK2 immunoreactivity. In contrast, 48 (20%) of 239 Type II tumors showed intense pCHK2 immunoreactivity. Ovarian surface epithelium, ovarian surface inclusion cyst, and tumor stromal tissues showed weak (1+) or undetectable levels of pCHK2 immunoreactivity.
Conclusions: Endometrioid and clear cell carcinomas of the ovary exhibit low levels of DNA damage and instability. Therefore, from the standpoint of DNA damage response, they belong in the Type I group of ovarian tumors.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 153, Wednesday Morning