**2. Genetics Features**

Genomic instability is universally considered as a driver of carcinogenesis, supporting the generation of all hallmarks of cancer (i.e., resistance to cell death, promotion of proliferative signaling, escape from growth suppressors, invasion and metastasis capacity, activation of replicative immortality, evasion of immune destruction, deregulation cellular energetics and neo-angiogenesis) [13,14]. Across several neoplasia, thyroid cancer presents lower genomic instability, expressed as the number of mutations per tumor, compared to other adult neoplasia (e.g., endometrial and colorectal cancers) [15]; this evidence has also been confirmed in metastatic cases [16]. However, thyroid cancer shows a heterogenous mutational burden across its histotypes: ATC presents an increased number of genetic alterations per tumor (median 4, range 0–29) compared to PTC and FTC [17]; likewise, according to data from Tissue Cancer Genome Atlas (TCGA), PDTC mutational burden is

higher than PTC, even if lower than ATC [18,19]. Genomic instability in PDTC and ATC embraces both somatic driver mutations and gene fusions.
