Telomere length in different histologic types of ovarian carcinoma with emphasis on clear cell carcinoma

Abstract

Ovarian carcinoma is composed of a heterogeneous group of tumors with distinct clinico-pathological and molecular features. Alteration of telomerase activity has been reported in ovarian tumors but the pattern of telomere length in their specific histological subtypes has not been reported. In this study, we performed quantitative telomere fluorescence in situ hybridization on a total of 219 ovarian carcinomas including 106 high-grade serous carcinomas, 26 low-grade serous carcinomas, 56 clear cell carcinomas and 31 low-grade endometrioid carcinomas. The mean relative telomere length of carcinoma to stromal cells was calculated as a telomere index. This index was significantly higher in clear cell carcinoma compared with the other histologic types (P=0.007). Overall there was no association between the telomere index and mortality, but when stratified by histologic types, the hazard ratio for death among women with clear cell carcinoma with a telomere index >1 was significantly increased at 4.93 (95% CI 1.64-14.86, P=0.005) when compared with those with a telomere index ≤1. In conclusion, our results provide new evidence that telomere length significantly differs by histologic type in ovarian carcinoma. Specifically, clear cell carcinomas have longer mean relative telomere lengths compared with the other histologic types and longer telomeres in clear cell carcinoma are associated with increased mortality suggesting that aberrations in telomere length may have an important role in the development and progression of this neoplasm.

Figure 1

Telomere index in different histological types of ovarian carcinoma. The telomere index is defined as the ratio of telomere fluorescence intensity of tumor cells to corresponding stromal cells. Each symbol represents an individual specimen and the average of the index is shown as a bar for each type. When the telomere index was categorized into two groups, (≤1 vs >1), clear cell carcinoma had more cases with a longer telomere (index >1) than the other types (P= 0.01, Fisher’s exact test). LGSC: low-grade serous carcinoma, HGSC: high-grade serous carcinoma, EMC: endometrioid carcinoma, CCC: clear cell carcinoma.

Figure 2

Representative images of telomere fluorescence in situ hybridization in different histological types of ovarian cancer. (a) Hematoxylin and eosin stained sections. (b) Telomere length is reflected by the total red fluorescence intensity in nuclei, which were counterstained with DAPI (blue florescence). In low-grade serous carcinoma (LGSC), high-grade serous carcinoma (HGSC) and endometrioid carcinoma (EMC) the stromal cells (filled arrows) show stronger red signal than carcinoma cells (open arrows) reflecting a smaller telomere index. In clear cell carcinoma (CCC), the carcinoma cells (open arrows) present longer telomere length as indicated by bigger, more numerous and intense red signal.

Figure 2

Representative images of telomere fluorescence in situ hybridization in different histological types of ovarian cancer. (a) Hematoxylin and eosin stained sections. (b) Telomere length is reflected by the total red fluorescence intensity in nuclei, which were counterstained with DAPI (blue florescence). In low-grade serous carcinoma (LGSC), high-grade serous carcinoma (HGSC) and endometrioid carcinoma (EMC) the stromal cells (filled arrows) show stronger red signal than carcinoma cells (open arrows) reflecting a smaller telomere index. In clear cell carcinoma (CCC), the carcinoma cells (open arrows) present longer telomere length as indicated by bigger, more numerous and intense red signal.

Figure 3

Kaplan–Meier survival curve analysis of telomere index in clear cell carcinomas. After adjusting for the patients’ age and clinical stage, patients with long telomeres (index >1) in their tumors had a worse overall survival than patients whose tumors had shorter telomeres (index ≤1) (P< 0.001, log rank test). The hazard ratio for death was 4.93 (95% CI 1.64–14.86 P= 0.005) for women with clear cell carcinomas with a higher telomere index (>1) compared with those women whose tumors had a smaller telomere index (≤1).