Abstract LB-343: Shortened telomeres in serous tubal intraepithelial carcinoma: An early event in ovarian high-grade serous carcinogenesis

Telomere shortening is one of the main genetic manifestations in human cancer which can contribute to initial chromosomal instability and ultimately tumor progression. The purpose of this study was to determine if changes in telomere length occur in serous tubal intraepithelial carcinoma (STIC), a putative precursor of “ovarian” high-grade serous carcinoma (HGSC). 22 STICs from 15 patients with concurrent HGSCs were analyzed by performing telomere-specific FISH and p53 immunofluorescence, to assist in identifying STICs. Telomere length in STICs was compared to HGSCs using normal fallopian tube epithelium (NFT), and stromal cells as controls. Telomeres length of these HGSCs was compared to 134 HGSCs, serving as a validation set. Immunostaining for Ki67, a proliferation index, and H2AX, a marker of DNA damage, was also performed. We found that STICs had the shortest telomeres, as 18 (82%) STICs had short telomeres, while 2 (9%) showed no change, and 2 (9%) had long telomeres compared to the NFT (Table 1). The majority of HGSCs also displayed shorter telomeres than the associated NFT. However, among 12 paired HGSCs and STICs, 7 HGSCs showed a significant increase in telomere length, 1 showed a decrease in length and 4 did not show any change when compared to their matched STICs. These differences between NFT and STICs, and between STICs and HGSCs were significant (p< 0.05). Finally, we found a weak correlation between telomere length in STICs and the percentage of H2AX positive cells (R2= 0.1021). In conclusion, the finding of shortened telomeres, which have been shown to be one of the earliest molecular changes in carcinogenesis, in the vast majority of STICs provides further support to the proposal that STICs are precursors of HGSC and opens new areas of research in elucidating the early events of ovarian high-grade serous carcinogenesis.Table 1:The relative telomere length in NFT, STIC, and HGSC in the same patients (SD, Standard Deviation; NA, Not Available).PatientSTICNFTSTICHGSCP-value STICP-value STICP-value HGSC nonoMeanSDMeanSDMeanSDcompared to NFTcompared to HGSCcompared to NFTKi67 (%)yH2AX (%)1Tl9.93.76.519.71.51.70.35670.174< 0.00019002T28.65.94.32.64.03.60.00060.7130.000660502T38.65.94.93.74.03.60.00510.3440.000640603T417.55.13.32.5NANA< 0.0001NANA503T517.55.16.83.3NANA< 0.0001NANA200 T622.07.87.04.514.26.6< 0.00010.0001< 0.000160100 T722.07.83.02.114.26.6< 0.00010.0001< 0.0001601005TS9.24.43.94.66.53.4< 0.00010.01570.010110906T93.92.236.16.144.011.9< 0.00010.002< 0.000120807T108.23.43.73.73.44.1< 0.00010.767< 0.0001301008Til14.712.70.80.95.83.9< 0.00010.0001< 0.0001801009T1217.210.19.05.48.04.60.00020.443< 0.000180NA9T1317.210.19.05.28.04.60.00020.443< 0.000180NA10T143.22.80.81.6NANA0.0001NANA1010010T153.22.81.51.6NANA0.0055NANA5010010T163.22.80.00.1NANA< 0.0001NANA504011T172.82.02.63.328.523.00.77750.0001 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-343.