title: Genetic and epigenetic background and protein expression profiles in relation to telomerase activation in medullary thyroid carcinoma.
abstract: Medullary thyroid carcinomas (MTCs) exhibit telomerase activation in strong association with shorter patient survival. To understand the background of telomerase activation we quantified TERT copy numbers and TERT promoter methylation in 42 MTCs and normal thyroid references. Gain of TERT was demonstrated by quantitative PCR in 5/39 sporadic MTC. Increased methylation index (MetI) for CpG methylation at the TERT promoter was found in sporadic MTCs (P < 0.0001) and in MEN 2 associated MTCs (P = 0.011) vs. normal thyroid tissues. MetI correlated positively with TERT gene expression (r = 0.432, P = 0.006) and negatively with telomere length (r = -0.343, P = 0.032). MTC cases with MetI above the median of 52% had shorter survival as compared to cases with lower MetI (P = 0.005 for overall survival and P = 0.007 for disease-related survival).Protein expression profiles obtained by mass spectrometry were then studied in relation to telomerase activation in MTCs. Comparing protein levels between tumors defined by telomerase activity status, 240 proteins were associated with telomerase activity. Among telomerase activation positive cases a set of proteins was found to discriminate between MTCs with high and low TERT gene expression with enrichment for proteins involved in telomerase regulation. XRCC5 mRNA expression was found increased in MTCs vs. normal thyroid (P = 0.007). In conclusion the findings suggest a role for TERT copy number gain, TERT promoter methylation and XRCC5 expression in telomerase activation and telomere maintenance of MTC.
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
authors: Na
authors: N
authors: Wang
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Solna, Sweden.
authors: Hanna
authors: H
authors: Kjellin
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
authors: Anastasios
authors: A
authors: Sofiadis
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
authors: Omid
authors: O
authors: Fotouhi
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
authors: C Christofer
authors: CC
authors: Juhlin
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors: Martin
authors: M
authors: Bäckdahl
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
authors: Jan
authors: J
authors: Zedenius
authors: Department of Medicine-Solna, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors: Dawei
authors: D
authors: Xu
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Solna, Sweden.
authors: Janne
authors: J
authors: Lehtiö
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
authors: Catharina
authors: C
authors: Larsson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D056915:DNA Copy Number Variations; D057890:Epigenomics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D020543:Proteome / Q000378:metabolism*; D015996:Survival Rate; D019098:Telomerase / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome; C509186:TERT protein, human; D019098:Telomerase; C106893:XRCC5 protein, human; D000072200:Ku Autoantigen
keywords: medullary thyroid carcinoma; methylation; proteomics; telomerase