Telomere Length in Different Histologic Types of Ovarian Carcinoma With Emphasis on Clear Cell Carcinoma

Elisabetta Kuhn; Alan K Meeker; Kala Visvanathan; Amy L Gross; Tian-Li Wang; Robert J Kurman ; Ie-Ming Shih

Disclosures

Mod Pathol. 2011;24(8):1139-1145. 

In This Article

Abstract and Introduction

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.

Introduction

Ovarian carcinoma, the most lethal gynecologic malignancy, is composed of several different histologic types.[1–3] A new dualistic model of carcinogenesis has been proposed, which provides a conceptual framework for studying this complex group of tumors based on clinicopathological and molecular genetic features.[4] Tumors are grouped into two broad categories designated type I and type II. Type I tumors include low-grade serous, low-grade endometrioid, clear cell and mucinous carcinomas that develop in a stepwise manner from well-established precursor lesions, such as endometriosis and borderline tumors.[5] Type II tumors are composed of high-grade serous carcinoma, carcinosarcoma and undifferentiated carcinoma and appear to develop from intraepithelial carcinomas in the fallopian tube.[6] Type I tumors are characterized by indolent behavior and harbor KRAS, BRAF, PIK3CA, CCNB1, ARID1A and PTEN mutations.[2] In contrast, type II tumors are highly aggressive and unlike the type I tumors have a very high frequency of TP53 mutations.[7,8] They rarely harbor the mutations that occur in the type I tumors and also differ molecularly from the type I tumors by having a high level of DNA copy number alterations.[9]

Telomeres are specialized chromosomal structures that are essential for maintaining the integrity of chromosomal ends. In normal cells, excessive telomere attrition triggers a DNA damage response that leads to cell cycle arrest. Cancer cells must maintain telomere integrity, either through telomerase-dependent or independent mechanisms, to continuously proliferate.[10] Although maintaining a certain telomere length is essential for tumor cell survival and progression, cancer cells also exploit telomere shortening, as exaggerated telomere shortening leads to telomere dysfunction and chromosomal instability by promoting abnormal fusion and rearrangement of chromosomes.[11] In fact, telomere shortening is an early event during tumor progression as it has been demonstrated in preinvasive lesions of several epithelial cancers, including prostate, breast and pancreatic carcinomas.[12] Similarly, we have recently demonstrated telomere shortening in the majority of serous tubal intraepithelial carcinomas, suggesting that it is one of the earliest molecular changes associated with the development of pelvic high-grade serous carcinoma.[13]

Given the important role of telomere biology in the pathogenesis of cancer development,[14] we hypothesized that telomere length might differ in type I and type II ovarian carcinomas considering their distinctly different molecular genetic features. Although telomerase gene expression and activity have been reported in ovarian cancer,[15–18] only a few previous studies have examined global telomere lengths by Southern blot in a small numbers of ovarian cancers.[19–22] The current study is notable in that it is the first to use direct in situ telomere assessment to comprehensively compare telomere length profiles among the major types of ovarian carcinoma and to correlate telomere length with the clinicopathological features of each type.

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