Abstract 221: TP53 mutations in serous tubal intraepithelial carcinoma, the putative precursor lesion of ovarian high-grade serous carcinoma

Abstract

Abstract Somatic mutation of TP53 is the most common molecular genetic alteration in high grade serous carcinoma (HGSC) of the ovary, occurring in more than 95% of cases. As serous tubal intraepithelial carcinomas (STICs) have been proposed to be the most likely precursor of HGSC, we undertook a study to determine whether STICs harbor TP53 mutations as well. Mutations of TP53 have been reported in STICs and associated HGSC but that study was limited to 5 cases. We therefore performed TP53 mutational analysis in a larger series of STICs and concurrent HGSCs and correlated the mutational status with p53 immunoreactivity. Formalin-fixed paraffin-embedded tissue specimens were obtained from 18 HGSCs with concurrent STICs; 8 of them contained two discrete STICs. Approximately 1,000 cells from STIC and normal-appearing fallopian tubal epithelium were laser-capture microdissected, while HGSCs were manually microdissected. Genomic DNA was extracted, PCR amplified and sequenced. TP53 mutations were analyzed from exons 4 to 8. Immunohistochemistry (IHC) for p53 was performed in all the cases. TP53 mutations were detected in 15 (83.3%) of 18 HGSCs. Importantly, TP53 mutations were not detected in the corresponding FTE samples from the same patients, confirming they are somatic mutations in HGSCs. STIC and associated HGSC shared identical TP53 mutations in 15 (93.8%) of 16 patients including 7 who had two STICs. The discordant case showed TP53 mutation in the HGSC but not in two separate concurrent STICs. By IHC, all the cases demonstrated the same pattern of p53 immunoreactivity (either all positive or completely negative) except the case with wild-type TP53 in the STIC and mutant TP53 in the HGSC. By IHC the STIC was p53 negative and the HGSC p53 positive. The three TP53 wild-type HGSCs and their associated STICs exhibited undetectable nuclear p53 by IHC. In contrast, four p53-negative HGSCs contained mutant TP53 with either a deletion or an insertion mutation. Our findings provide cogent evidence that TP53 mutations occur in most STICs, and that both STIC and concurrent HGSC share the identical TP53 mutations in the majority of cases. Future molecular genetic studies are necessary to delineate the clonal relationship and tumor progression from STIC to HGSC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 221. doi:10.1158/1538-7445.AM2011-221