Genetic and epigenetic background and protein expression profiles in relation to telomerase activation in medullary thyroid carcinoma
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Na Wang1,2, Hanna Kjellin1,3,4, Anastasios Sofiadis1,2, Omid Fotouhi1,2, C. Christofer Juhlin1,2, Martin Bäckdahl3, Jan Zedenius3, Dawei Xu5, Janne Lehtiö1,4, Catharina Larsson1,2
1Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
2Cancer Center Karolinska, Karolinska University Hospital R8:04, SE-171 76 Stockholm, Sweden
3Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
4Science for Life Laboratory, SE-171 21 Solna, Sweden
5Department of Medicine-Solna, Division of Hematology and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden
Na Wang, e-mail: [email protected]
Keywords: medullary thyroid carcinoma, methylation, proteomics, telomerase
Received: July 13, 2015 Accepted: January 17, 2016 Published: February 08, 2016
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.
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