Abstract
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 BRAFV600E 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 BRAFV600E 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.
Highlights
Genomic analysis of cancer samples reveals a complex mutational landscape with vast intertumor and intratumoral heterogeneity
The present review reports and discuss the data published in the literature related to the impact of Intratumoral heterogeneity (ITH) in the origin and progression of papillary thyroid cancer (PTC), which accounts for almost 80% of all TC cases, and to the diagnostic and clinical implications related to this phenomenon
Mutation is frequently an oligoclonal event [57]. This data was confirmed by Gandolfi et al [7] who showed by pyrosequencing in 58 BRAFV600E -positive papillary thyroid carcinoma (PTC), an average mutated allele percentage of 27.44%, with a range between 7.50% and 49.80%
Summary
Genomic analysis of cancer samples reveals a complex mutational landscape with vast intertumor and intratumoral heterogeneity. ITH is likely to be the consequence of either the presence of two mutations in different clones in the primary tumor and to the distant propagation of only one clone, or to the acquisition of a secondary event at the metastatic site [7] In this context, it would be critical to identify the cancer cells that have the potential to contribute to disease progression, in order to develop more effective cancer therapies. The second mechanism is a paradigm of the carcinogenesis and the most accepted theory of thyroid tumor development, i.e., the stochastic multistep model, which is based on the theory of cancer clonal evolution [13] This model states that tumor formation is a consequence of genome instability within somatic cells, which can lead to the appearance of more aggressive clones able to survive the selection pressure of the microenvironment and to outcompete other cells. The present review reports and discuss the data published in the literature related to the impact of ITH in the origin and progression of papillary thyroid cancer (PTC), which accounts for almost 80% of all TC cases, and to the diagnostic and clinical implications related to this phenomenon
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