TERT copy number, methylation hold prognostic value for medullary thyroid carcinoma

LAKE BUENA VISTA, Fla — TERT copy number gains and increased promoter methylation appeared associated with telomerase activation in patients with medullary thyroid carcinoma, according to study results presented at the International Thyroid Congress.

The quantification of TERT methylation may, thus, serve as a prognostic marker in medullary thyroid carcinoma, the researchers reported.

Medullary thyroid carcinoma is a rare and aggressive subset of thyroid cancer originating in thyroid C cells. Telomerase — a ribonucleoprotein complex — plays a critical role in telomere maintenance and cancer biology, according to study background.

Na Wang, a PhD student in the department of oncology and pathology at Karolinska Institutet in Stockholm, and colleagues conducted a prior study in which they observed activation of telomerase in approximately half of patients with medullary thyroid carcinoma, which they strongly associated with worsened survival outcomes. However, TERT promoter mutations were not revealed.

Thus, researchers conducted the current analysis to evaluate telomerase activation, TERT copy numbers and TERT promoter methylation in medullary thyroid carcinoma compared with normal thyroid references.

The study included data from 42 patients with medullary thyroid carcinoma (sporadic, n = 39; MEN2, n = 3).

The researchers used a quantitative real time polymerase chain reaction-based copy number assay to explore copy number status of TERT in the patient cohort. Pyrosequencing was used to quantify TERT promoter methylation.

Five of 21 patients with medullary thyroid carcinoma with telomerase activation exhibited TERT copy number gain; all other cases exhibited two copy numbers for TERT.

Further, 37 patients with sporadic medullary thyroid carcinoma exhibited significantly increased methylation index (MetI) for methylation at the TERT promoter (MetI, 12%-90%) compared with normal thyroid references (MetI, 6-8%; P < .0001).

MetI correlated positively with TERT gene expression (r = 0.432; P = .006) and negatively with telomere length (r = 0.343, P = .032). MetI also appeared associated with the presence of a RAS mutation (P = .031).

Patients with MetI less than 52% had shorter OS compared with patients with MetI of at least 52%.

In an analysis of the effect of telomerase activation on protein expression profiles, the researchers identified and quantified 4,321 proteins, including 240 that were differentially expressed between medullary thyroid carcinomas that were positive and negative for telomerase activation.

“The findings suggest that TERT copy number gain and increased promoter methylation are associated with telomerase activation in medullary thyroid cancer,” Wang and colleagues wrote. “Quantification of TERT methylation could be considered as a prognostic marker in medullary thyroid cancer.” – by Cameron Kelsall

Reference:

Wang N, et al. Short Oral Communication 490. Presented at: International Thyroid Congress; Oct. 18-23, 2015; Lake Buena Vista, Fla.

Disclosure: The researchers report no relevant financial disclosures.