## 1 Introduction  
Mutations in the proximal promoter of _TERT_ (telomerase reverse transcriptase) are the first genomic lesions in a gene regulatory region and display a high prevalence across multiple cancer types [1]. They were first identified in cutaneous melanoma [2; 3] and subsequently reported in numerous malignancies [4], including thyroid carcinomas [5; 6]. _TERT_ promoter mutations (TPMs) are observed with increasing frequency according to the severity of thyroid cancer [7; 8]. Thus, only 9% of the papillary thyroid cancers (PTCa), a predominant subtype with overwhelmingly good prognosis, harbor TPMs, and these are typically subclonal within the tumor [9]. In contrast, we reported that TPM prevalence is much higher in advanced thyroid tumors, which account for most of the morbidity and mortality of the disease: they occur in 40% of poorly differentiated (PDTC) and 73% of anaplastic thyroid cancers (ATC) [8]. Within each thyroid tumor subtype, TPMs associate with more aggressive features, particularly in combination with constitutive activation of the MAPK (\"mitogen-activated protein kinase\") pathway, usually via BRAFV600E driver mutation [8; 10; 11]. Overall, this stepwise increase in frequency implies that clonal TPMs confer a strong selective advantage as PTC progresses to PDTC/ATC. TPMs occur at either c-124C>T or c-146C>T in a mutually exclusive fashion. These single nucleotide substitutions generate an identical 11-nucleotide stretch creating de novo binding sites for the ETS (\"E26 transformation specific\") family of transcription factors, which comprise 27 members with diverse functions and tissue-specific roles [12]. As a result, _TERT_ transcription, which is typically silenced in adult tissues, is reactivated in cells carrying TPMs. The seminal papers reporting TPMs in melanoma pointed at an ETS-mediated role on _TERT_ mutant promoter control [2; 3], but the identification of the specific factors involved in this regulation, particularly in thyroid cancers, has proven not to be straightforward. Nevertheless, distinguishing which ETS (and other) factors are important in the reactivation of _TERT_ in aggressive thyroid tumors is a necessary first step towards enabling new methods of blocking _TERT_ expression and ultimately inhibiting cell growth in a cancer-specific manner. Several studies in _TERT_-mutant glioblastomas demonstrated that GABPA, an ETS factor acting as a tetrameric protein along with its GABPB isoform, drives _TERT_-mutant transcription in this tumor lineage, opening the door to targeting the GABPA/GABPB axis to achieve _TERT_ downregulation in that context [13; 14; 15]. The former prompted the _a priori_ attractive idea of GABPA also being the key player in _TERT_-mutant regulation across TPM-harboring thyroid cancers [16]. However, several other ETS members, including ELK1 and ETV1/4/5, have been proposed to control _TERT_ transcription in thyroid specimens [11; 17; 18], suggesting that promiscuity and/or compensatory mechanisms among ETS and possibly other proteins exist. A recent study showed that GABPA has tumor suppressor properties in thyroid tumors, rendering this factor an unadvisable target for inhibition in this lineage [19]. In addition, some ETS proteins as well as other MAPK-mediated factors such as Sp1 and c-Myc are also able to bind and control the _TERT_ wildtype promoter [20; 21; 22; 23]. Thus far, most thyroid cancer studies aimed at identifying mechanistic underpinnings of _TERT_ mutant control have either focused on single ETS factors in several cell lines or screened multiple factors in a limited number of lines. Here, we adopted an agnostic approach, screening all ETS factors that are expressed in thyroid tumors in numerous, fully characterized, thyroid cancer cell lines. Our results point to a greater complexity of TPM-mediated regulation of _TERT_ transcription from what was previously reported and caution against adopting what has been demonstrated in other cancer types carrying TPMs into thyroid tumors.