Biomarkers of Rb Signaling Loss Are Characteristic of High Grade Adnexal Serous Carcinoma
PA Shaw, A Chun, A Milea, A Tone, H Begley, J Greenaway. University Health Network, Toronto, ON, Canada
Background: Overexpression of p16, a tumor suppressor gene, is frequent in ovarian cancer, and as a response to cellular stress in a cell with intact p16/Rb signaling, will result in proliferation arrest. A compromised Rb pathway however will lead to increased p16 expression and continued proliferation. This study proposes to determine the differential expression of p16/Rb pathway genes in ovarian cancer, as assessed by expression profiling and protein expression by immunohistochemistry, and to determine if alterations in the p16/Rb pathway predict for histologic type and clinical outcome.
Design: All carcinomas, tissues, and tissue microarrays were identified and retrieved through the UHN Biobank. Differential gene expression of p16, cyclin D1, Rb, cyclin E, and E2F transcription activators in high grade serous carcinomas (HGSC) and normal tubal epithelium (FTE) was determined after profiling microdissected normal tubal epithelium and 13 high grade serous carcinomas using Affymetrix U133 Plus 2.0 arrays. Immunohistochemistry for p16, cyclin D1, and MIB1 was performed using standard techniques. Stained tissue microarray sections, representing 468 ovarian tumors, were digitally scanned, and protein expression scored according to percentage tumor cells positive and staining intensity, with their sum determining the final histoscore. Fisher's exact test with 95% confidence intervals was used to determine the significance of results.
Results: Expression profiles revealed significantly increased expression of p16, E2F1, E2F3, and cyclin E genes in HGSC compared to normal FTE (p<0.05). Cyclin D1 was down regulated in cancers, and there was no significant change in Rb1 gene expression. By IHC, p16 was overexpressed in both serous (80%) and non-serous carcinomas (36%), but a high p16/high MIB1 signature was significantly more common in HGSC than in non-serous cancers (p=0.003).
Conclusions: High grade serous carcinoma has increased p16 expression, and expression profiles indicate this is often associated with decreased cyclin D1, increased cyclin E, and increased E2F transcription activators, reflecting compromised Rb signaling, and allowing cells to bypass senescence and increase proliferation. Preliminary protein expression data suggest that overexpression of p16 in a nonfunctional Rb pathway may be a potential biomarker of HGSC.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 217, Tuesday Morning