Abstract 3783: High resolution telomere FISH analysis of testicular germ cell tumors reveals telomere anomalies specific to cancer subtypes and demonstrates telomere shortening as an early event in TGCT carcinogenesis

Abstract

Abstract Testicular germ cell tumor (TGCT) is the most common malignancy of young men between 15 and 40 years of age. TGCT is exceptional, as most men can be completely cured. We evaluated 76 TGCT cases using high resolution (single-cell) telomere-specific fluorescence in situ hybridization (FISH) combined with Oct4 immunofluorescence staining to delineate telomere length patterns in different TGCT subtypes, as well as in the precursor lesion, intratubular germ cell neoplasia unclassified type (ITGCNU). Telomere lengths were qualitatively scored by comparing the intensity of the telomere signals from cancer cells to benign reference cell types and then grouped (short, medium, and long). For isolated tumors and for those part of a mixed germ cell tumor (containing 2 or more TGCT types), we determined the overall trends in telomere length in comparison to reference cell populations. This comparison demonstrated medium telomeres for normal germ cells, short telomeres for ITGCNU and seminomas (p = 0.006 and p = 0.0005, respectively), and a wide range of average telomere lengths in the non-seminomas. Among the non-seminomas, embryonal carcinomas displayed the longest telomeres, on average, and were the only subtype (27% of cases) to display the alternative lengthening of telomeres (ALT) phenotype, as evident from abnormally large telomeric foci and telomere length heterogeneity. ATRX and DAXX protein expression was not absent in a subset of embryonal carcinoma cases. Compared to somatic tissues, germ cells have a high basal telomerase activity and longer telomeres. Hence, short telomeres in ITGCNU are surprising. Telomere attrition does not occur in normal germ cells; therefore, telomere shortening in ITGCNU may play a role in TGCT tumorigenesis. Embryonal carcinoma, the TGCT subtype that is most aggressive and has the worst prognosis, showed very long telomeres. Seminomas, with short telomeres, are exquisitely sensitive to standard platinum based chemotherapy. A recent study implicates telomere damage as a consequence of platinum based chemotherapeutic agents in a male germ cell line. Thus, the knowledge of telomere length differences and that of chemotherapeutic agents’ damage to telomeres together may help shed light on the differential sensitivities of TGCT subtypes to certain chemotherapeutic agents. In summary, TGCT can demonstrate varied telomere lengths depending on lesion subtype and whether the lesion occurs in the context of a mixed tumor. The presence of short telomeres in ITGCNU suggests a major role of telomere shortening in the pathogenesis of TGCT. In the future, telomere length information may also inform point-of-care diagnostic and treatment decisions for clinicians caring for TGCT patients. Citation Format: Mohammed T. Shekhani, John Barber, Christopher M. Heaphy, Leonardo Reis, Gunes Guner, Corinne Joshu, George J. Netto, Alan K. Meeker. High resolution telomere FISH analysis of testicular germ cell tumors reveals telomere anomalies specific to cancer subtypes and demonstrates telomere shortening as an early event in TGCT carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3783. doi:10.1158/1538-7445.AM2015-3783