Upregulation of Potential Oncogenes in Serous Tubal Intraepithelial Carcinoma (STIC)
AE Smith Sehdev, RJ Kurman, E Kuhn, IM Shih. Cascade Pathology, Portland, OR; Johns Hopkins Medical Institution, Baltimore
Background: STIC has been proposed as a precursor for many pelvic high-grade serous carcinomas (HGSC). Our previous analysis of the ovarian cancer genome identified several genes with oncogenic potential that are amplified and/or overexpressed in the majority of HGSC. Determining whether these genes are upregulated in STIC is important in further elucidating the relationship of STIC to HGSC and is fundamental in understanding the molecular pathogenesis of HGSC.
Design: 35 morphologically defined STICs were obtained from 24 patients with stage IIIC/IV HGSC. All STICs were discrete from the HGSC. Both STIC and the HGSC were analyzed for expression of ovarian cancer-associated markers including Rsf-1 (chromatin remodeling gene), fatty acid synthase (FASN, enzyme involved in fatty acid synthase), cyclin E (cell cycle protein) and mucin-4 (CA125 binding protein and signal transducer). These four proteins were selected because they have been shown to participate in the pathogenesis of HGSC. In addition, STICs and HGSC were examined for expression of conventional markers including p53, Ki-67 and p16. The percentage of intensely immunoreactive nuclei was determined for p53, Ki-67, p16 and cyclin E while a three-tier intensity score was used to compare the immunoreactivity of Rsf-1, FASN and mucin-4 in STIC to adjacent normal-appearing tubal epithelium. In a few STICs the lesions were not present in deeper sections for some markers.
Results: Diffuse nuclear p53 and p16 immunoreactivity (>50% of nuclei) was observed in 25 (69%) of 36 and 14 (45%) of 31 STICs, respectively, while an elevated Ki-67 labeling index (≥5%) was detected in 34 (94%) of 36 STICs. Among the STICs with diffuse p53 immunoreactivity, 23 (92%) of 25 STICs displayed an elevated Ki-67 labeling index (≥5%). Cyclin E nuclear staining was seen in 25 (71%) of 35 STICs while normal tubal epithelial cells were all negative. Increased Rsf-1, FASN and mucin-4 immunoreactivity as compared to adjacent normal-appearing tubal epithelium occurred in 69%, 66% and 54% of STICs, respectively. Almost all HGSC showed the same staining patterns as the STICs.
Conclusions: STICs express several potential oncogenes that are frequently amplified and/or upregulated in HGSC. Their frequency of overexpression is similar to that found in a large series of HGSC previously reported. These results provide additional evidence that STICs are possible precursors of HGSC and suggest that overexpression of Rsf-1, cyclin E, FASN and mucin-4 occurs early in tumor progression of HGSC.
Category: Gynecologic & Obstetrics
Tuesday, March 23, 2010 9:15 AM
Platform Session: Section D, Tuesday Morning