Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma.
BACKGROUND
Telomere maintenance via telomerase activation and the alternative lengthening of telomeres (ALT) mechanism was assessed in medullary thyroid carcinoma.


METHODS
In total, 42 medullary thyroid carcinomas (MTC) were studied including 24 rearranged during transfection (RET)- mutated cases. Relative telomerase reverse transcriptase (TERT) expression, splice forms, and telomere length were determined by PCR-based methods, and telomerase activity by ELISA. The ALT mechanism was detected by Southern blot analysis and immunofluorescence.


RESULTS
TERT expression and telomerase activity were detected in 21/42 tumors (50%), and was independent of the common somatic M918T RET mutation. Mean telomere length was shorter in MTCs compared with thyroids. Telomerase activation was associated with large tumor size (P = .027), advanced clinical stage (P = .0001), and short survival (P = .0001). Full-length TERT and the α(-) and β(-)-deletion forms were revealed, and the full-length form was associated with short survival (P = .04). A subset of cases without telomerase activation showed involvement of the ALT mechanism, which was associated with a low MIB-1 proliferation index (P = .024).


CONCLUSIONS
Stabilization of telomeres by telomerase activation occurs in half of the MTCs and by the ALT mechanism in a subset of cases. Telomerase activation may be used as an additional prognostic marker in medullary thyroid carcinoma.
Department of Oncology-Pathology (N.W., A.S., A.H., C.L.), Department of Medicine, Division of Hematology (D.X.), Department of Clinical Neuroscience, Center for Molecular Medicine (V.V.), Department of Molecular Medicine and Surgery (M.B., J.Z.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; Cancer Center Karolinska (N.W., A.S., A.H., C.L.), Department of Pathology-Cytology (A.H.), Department of Breast and Endocrine Surgery (M.B., J.Z.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden.
Na
N
Wang
Dawei
D
Xu
Anastasios
A
Sofiadis
Anders
A
Höög
Vladana
V
Vukojević
Martin
M
Bäckdahl
Jan
J
Zedenius
Catharina
C
Larsson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018278:Carcinoma, Neuroendocrine; D004252:DNA Mutational Analysis; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D016615:Telomere / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D055815:Young Adult
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D019098:Telomerase