2222P - Frequent TERT gains in metastatic papillary thyroid carcinoma

Background

TERT (Chr.5p15) is one of the most relevant biomarkers in thyroid cancer aggressiveness, including metastatic papillary thyroid carcinomas (mPTCs). The TERT promoter mutations (TPM) rate in mPTCs is 45-60%. Chromosomal gains at 5p have also been reported in thyroid cancer, however little is known about the specific prevalence of TERT copy number variations (CNV) in mPTCs and its putative role in tumor prognosis.

Methods

By genotyping 38 cases of primary PTCs and matched distant (DM) and/or lymphatic metastases (LNM), we sought to determine the prevalence of TPM and CNV, their coexistence, and their association with other driver mutational events in thyroid cancers. 114 areas were analyzed to tackle the contribution of intratumoral heterogeneity (ITGH) and clonal evolution to metastases. Mutational analysis was approached through PCR-SSCP or direct sequencing. Ligation-dependent probe amplification was used to assess TERT CNV.

Results

TERT was altered in 37 cases. Gains were more common than TPM (94,6% vs 45,9%). Both features coexisted in 40,5% of the cases. The study of ITGH evidenced that 66,6% and 20% of the cases bearing both, TPM + CNV, were concurrently mutated at BRAF and RAS respectively. The coexistence of both events or TPM alone correlated significantly with the stage at diagnosis (dx) and stage at follow-up (Fup), patient status (DOD, AWD, NED), age ≥ 55, and sex or showed a trend of correlation with LNM at Fup. TPM were as well significantly associated with LNM at dx and tumor recurrences, revealing a trend for an association with vascular invasion, DM, and DM at Fup too. CNV were more frequently clonal than TPM (85,7% vs 52,9%).

Conclusions

The prevalence of TERT gains in mPTCs is strikingly higher than in other cohorts of nonaggressive PTCs, such as TCGA. TERT gains tend to be more clonal than TPM. TERT CNVs seemingly represent an earlier event than TPM in mPTC. The coexistence of both events strengthens the association of TPM with poor prognostic features and tumor aggressiveness.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Valladolid University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.