Abstract

BACKGROUNDKeratin 17 (K17) is a negative prognostic biomarker in cervical and ovarian cancers but has not previously been evaluated as a prognostic biomarker in endometrial adenocarcinoma. The association of K17 with decreased patient survival may be explained in part by the recent discovery that K17, unique among all keratins, drives tumor aggression by serving as a nuclear shuttle of p27, leading to cell cycle progression. Analysis of gene expression data from The Cancer Genome Atlas (TCGA) demonstrated that high K17 mRNA expression is prognostic for decreased overall survival in patients with endometrial carcinoma (n=228), prompting to test in the current study the hypothesis that immunohistochemical (IHC) staining for K17 correlates with survival of patients with endometrial cancer.METHODSCases of endometrial carcinoma were selected from Stony Brook Medicine Cancer Registry and UMass Memorial Cancer Registry. Histologic subtypes included endometrioid carcinoma (n=81), serous carcinoma (n=44), clear cell carcinoma (n=37), and malignant mixed Müllerian tumor (MMMT) (n=48). K17 was detected in sections of formalin‐fixed, paraffin‐embedded tissue blocks by indirect immunoperoxidase methods. Staining was scored based on the proportion of tumor cells that showed strong staining for K17 (PathSQ Score). Cases with “high‐K17” were defined as those with PathSQ score ≥10% and “low‐K17” cases were those with PathSQ <10% of tumor cells. Survival analyses were determined using the Kaplan‐Meier method and Mantel‐Haenszel method.RESULTS AND DISCUSSIONHigh‐K17 was detected in 31/210 cases of endometrial carcinoma, including 18/81 endometrioid carcinomas, 5/37 clear cell carcinomas, 6/44 serous carcinomas, and 17/48 MMMTs. Staining was localized to the malignant epithelial component in each case and was not detected in benign stromal cells, myometrium, or sarcomatous elements of MMMTs. Overall, High‐K17 correlated with decreased patient survival (HR: 4.8, n=210, p=0.0002). This trend was also found in clear cell carcinoma, serous carcinoma, and MMMT subtypes. K17 expression was also independently prognostic for both cases with localized (HR: 6.8, p=0.0009) and metastatic disease (HR: 2.4, p=0.0625), as well as for high‐grade tumors (HR: 2.3, p=0.0142), across all histologic subtypes of endometrial carcinoma.Prognostic biomarkers for endometrial adenocarcinoma have the potential to identify patients that are most likely to benefit from aggressive surgical intervention, including complete staging at the time of primary resection. The results of this study support the hypothesis that K17 is a powerful negative prognostic biomarker for not only high‐grade endometrioid adenocarcinomas, but also for other high‐grade histologic types of uterine carcinoma and MMMT, including cases limited to the uterus and those with advanced stage disease. Further studies are indicated to address the potential role of K17 as prognostic biomarker, to inform patient treatment decisions.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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