Abstract 1193: Identical TP53 mutations support a common origin for mixed histology epithelial ovarian cancer.
Authors: Erickson Britt K. , Dobbin Zachary C. , Shim Eun-Hee , Alvarez Ronald D. , Conner Michael G. , Landen Charles N. 
Published: August 2014

Background: Traditionally, epithelial ovarian cancer (EOC), and its various histologic subtypes, was considered one disease process. With an improved understanding of underlying carcinogenesis, it is now hypothesized that ovarian cancers of different histologies may originate in different sites - serous from the fallopian tube, endometrioid and clear cell from endometriotic implants, and mucinous from the GI tract. However, five percent of EOC are classified as “mixed” tumors, with two or more histologic subtypes present in the same tumor. Whether these cancers represent phenotypic diversions of the same cancer, or synchronous tumors from different sites is not known, and if discovered, may shed light on the etiology of single-histology malignancies.

Objective: By comparing the TP53 mutational signatures of both histologic subtypes within the same tumor, we sought to determine if mixed histology ovarian cancers arise from the same tumor initiating cells.

Methods: After IRB approval, formalin fixed paraffin embedded samples of mixed histology tumors were identified. After review by a gynecologic pathologist, the specific area of each histologic subtype was identified and isolated using Laser Capture Microdissection (LCM). DNA was extracted separately from each histologic subtype. PCR reactions were performed to amplify TP53 exons 4-8. Gel electrophoresis was performed to specifically isolate the desired exon, which was extracted and purified for sequencing. Sanger sequencing was performed in forward and reverse directions, and mutations were identified by comparison to the TP53 reference sequence (NC_000017). TP53 mutations were compared between both histologic subtypes of the same tumor sample to assess for clonality.

Results: 10 patients were identified with mixed histologies and subjected to LCM. Extracted DNA was of sufficient quality to sequence both histologies in 9 patients. Thus far, 4 patients samples have been sequenced and analyzed. In one patient no TP53 mutation was identified. In the remaining 3, a single mutation was found, and was identical in both histologic sections. All mutations were missense. The TP53 mutations identified in these samples had all previously been described, supporting the validity of identified mutations. These findings support additional sequencing of the remaining 5 patients.

Conclusions: These analyses suggest that the separate components of mixed histology epithelial ovarian cancer harbor the same early TP53 mutations - supporting their clonality. This supports the hypothesis that that mixed histology EOC tumors originate from the same tumor initiating cell, and that not all histologic subtypes of non-mixed ovarian cancers may have separate origins.

Citation Format: Britt K. Erickson, Zachary C. Dobbin, Eun-Hee Shim, Ronald D. Alvarez, Michael G. Conner, Charles N. Landen. Identical TP53 mutations support a common origin for mixed histology epithelial ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1193. doi:10.1158/1538-7445.AM2013-1193