Anaplastic thyroid cancer (ATC) is a rare, lethal disease associated with a median survival of 6 months despite the best multidisciplinary care. Surgical resection is not curative in ATC patients, being often a palliative procedure. Multidisciplinary care may include surgery, loco-regional radiotherapy, and systemic therapy. Besides conventional chemotherapy, multi kinase-targeted inhibitors are emerging as novel therapeutic tools. The numerous molecular alteration detected in ATC are targets for these inhibitors. The aim of this review is to determine the prevalence of the major genetic alterations occurring in ATC and place the results in the context of the emerging kinase-targeted therapies.

Background: The tyrosine kinase receptors/RAS/RAF/MAPK cascade is a site of mutational events associated with thyroid carcinogenesis. Some studies suggest the reciprocal exclusion of different oncogenes in the mitogen-activated protein kinase cascade, whereas others suggest that BRAF mutations and RET rearrangements can simultaneously occur in sporadic cases. The aim of this study was to determine the prevalence of concomitant BRAF ^V600E mutation and RET/PTC rearrangements in the same tumor and its association with some clinicopathological features. Methods: The percentage of mutant BRAF alleles and the presence of RET/PTC rearrangements were determined by means of pyrosequencing and Southern blot analysis of reverse transcription polymerase chain reaction products in a series of 72 conventional papillary thyroid carcinomas (PTCs). Then, the associations between clinicopathological characteristics and mutation status were assessed. Results: BRAF ^V600E alleles were present in 32 out of 72 PTCs (44.4%) in the range of 5.1–44.7% of total BRAF alleles. RET/PTC was present in 26 tumors (36.1%). Concomitant subclonal BRAF and RET/PTC were demonstrated in 14 PTCs (19.4%), and none of the oncogenes was detected in 22 tumors (30.5%). Only BRAF ^V600E was associated with a more advanced tumor staging. Conclusions: The present study demonstrates that concomitant BRAF mutation and RET/PTC rearrangement is a frequent event in PTC.

Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.

Intratumoral heterogeneity (ITH) refers to a subclonal genetic diversity observed within a tumor. ITH is the consequence of genetic instability and accumulation of genetic alterations, two mechanisms involved in the progression from an early tumor stage to a more aggressive cancer. While this process is widely accepted, the ITH of early stage papillary thyroid carcinoma (PTC) is debated. By different genetic analysis, several authors reported the frequent occurrence of PTCs composed of both tumor cells with and without RET/PTC or BRAF^V600E genetic alterations. While these data, and the report of discrepancies in the genetic pattern between metastases and the primary tumor, demonstrate the existence of ITH in PTC, its extension and biological significance is debated. The ITH takes on a great significance when involves oncogenes, such as RET rearrangements and BRAF^V600E as it calls into question their role of driver genes. ITH is also predicted to play a major clinical role as it could have a significant impact on prognosis and on the response to targeted therapy. In this review, we analyzed several data indicating that ITH is not a marginal event, occurring in PTC at any step of development, and suggesting the existence of unknown genetic or epigenetic alterations that still need to be identified.