Telomerase activity and telomere length in thyroid neoplasia: biological and clinical implications

Abstract

Despite several recent studies, the biological status and clinical relevance of telomerase expression in tumours derived from the thyroid follicular cell remain controversial. This study has analysed a series of normal, benign, and malignant thyroid samples using two novel approaches: the use of purified epithelial cell fractions to eliminate false-positives due to telomerase-positive infiltrating lymphocytes; and the simultaneous measurement of telomere length to provide a clearer interpretation of telomere dynamics in thyroid neoplasia. The data obtained support the prediction that the epithelial component of non-neoplastic thyroid and of follicular adenomas is telomerase-negative, any positive results being explicable by lymphocyte infiltration. In contrast, many malignant tumours, both follicular and papillary, were telomerase-positive. However, serial dilution of extracts indicated a wide spectrum of activity in these cancers, possibly related to variation in the proportion of telomerase-positive cells. Furthermore, an unexpectedly high proportion were telomerase-negative, a finding which was not explicable by technical problems such as TRAP (telomeric repeat amplification protocol) assay sensitivity. Many of these apparently telomerase-negative tumours had abnormally long telomeres. Correlation of telomerase and telomere length data suggests that thyroid cancers fall into three biological groups: telomerase-positive lesions, consistent with the conventional model of telomere erosion followed by telomerase reactivation; telomerase-negative tumours, which maintain telomere length by a mechanism independent of telomerase; and telomerase-negative tumours which are still undergoing telomere erosion and may therefore be composed of mortal cancer cells. From a clinical standpoint, it is concluded that telomerase detection on unfractionated tissue, such as fine needle aspirates, is of no value as a marker of malignancy in follicular lesions, due to both low sensitivity and specificity.

Alternative lengthening of telomeres in mammalian cells

“…For reasons which are also unclear, there are a few types of carcinomas that appear to have a relatively low incidence of telomerase positivity. For example, of a total of 237 papillary thyroid carcinomas described in 12 reports 53% did not have detectable telomerase activity (Aogi et al, 1998(Aogi et al, , 1999Brousset et al, 1997;Cheng et al, 1998;Haugen et al, 1997;Kammori et al, 2000;Lo et al, 1999;Matthews et al, 2001;Okayasu et al, 1997;Saji et al, 1997Saji et al, , 1999Yashima et al, 1997). How many of these have ALT is currently unknown.…”

“…A number of studies have attempted to use the presence of telomerase activity to distinguish benign from malignant tumors (Hiraga et al, 1998;Kammori et al, 2000;Matthews et al, 2001;Saji et al, 1997;Yashima et al, 1997). It is possible that the correlations would be improved if ALT were also taken into account.…”

Clinical utility of telomerase in cancer

“…However, telomerase activity is also detected in some kinds of normal cells, especially in proliferative stem cells and activated lymphocytes (Hiyama et al, 1995c(Hiyama et al, , 1996bWright et al, 1996) and this can complicate the interpretation of the TRAP results. In addition, some benign tumors such as ®broadenomas of the breast (Hiyama et al, 1996a), hyperplastic nodule/adenomas of the thyroid (Matthews et al, 2001) and colon adenomas (Hiyama et al, 1996b) also have detectable telomerase activity. Since the activity levels in these benign tumors are low, quantitative analysis of telomerase activity is necessary to distinguish the upregulation of telomerase in cancer cells.…”

“…Nipple discharge (ductal lavage) may also become a useful and less invasive material for cancer cell detection (Leris et al, 2000). In thyroid tumors, for which FNA is a usual diagnostic tool, benign tumors such as follicular adenoma, Graves disease, and Hashimoto disease also show telomerase activity (Matthews et al, 2001). Although the speci®city of telomerase activity for thyroid cancer is low, it may be useful for cancer diagnosis with the combination of cytology.…”

“…Telomerase activity is a useful indicator to determine malignant grade in the group of tumors in which benign and malignant tumors are sometimes indistinguishable by morphological examination such as brain tumors (Falchetti et al, 1999;Langford et al, 1997), papillary adenocarcinoma in thyroid (Matthews et al, 2001), pancreatic endocrine tumors (Pearson et al, 2000), urothelial cell carcinoma (Lancelin et al, 2000), and cervical intraepithelial neoplasia (Wisman et al, 2001). In these tumors, the levels of telomerase activity subsequently correlated to the prognosis of the patients.…”