Intratumoral Genetic Heterogeneity in Papillary Thyroid Cancer: Occurrence and Clinical Significance

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.

Analytical and clinical validation of pairwise microRNA expression analysis to identify medullary thyroid cancer in thyroid fine‐needle aspiration samples

“…Both MTC and non-MTC neoplasms manifest intratumoral heterogeneity, in which somatically acquired mutations are present in only a subset of tumor cells. 41,42 When the overall mutation variant percentage is relatively low, the FNA sample may capture a percentage of mutated cells that falls beneath the lower limit of mutation detection, leading to a false-negative mutation testing result. This false-negative result is less likely to occur with the use of miRNA analysis because the miRNAs can be present in mutation-negative cells.…”

“…From a diagnostic perspective, this is especially valuable with respect to sampling variations related to needle aspiration of discrete microscopic sites within a relatively large‐sized nodule. Both MTC and non‐MTC neoplasms manifest intratumoral heterogeneity, in which somatically acquired mutations are present in only a subset of tumor cells 41,42 . When the overall mutation variant percentage is relatively low, the FNA sample may capture a percentage of mutated cells that falls beneath the lower limit of mutation detection, leading to a false‐negative mutation testing result.…”

Effect of TTLL12 on tubulin tyrosine nitration as a novel target for screening anticancer drugs<em> in&nbsp;vitro</em>

“…Chemotherapy, as the only effective systemic treatment, began in 1948 (folic acid antagonists were used as antitumor drugs to treat leukemia), which plays an irreplaceable role in the comprehensive treatment of cancer ( 47 ). Due to the heterogeneity of tumors ( 48 ), different individuals have different reactions to the same drug, which affects the treatment outcome. In response to this problem, some medical studies have proposed to use a drug sensitivity experiment to provide individualized treatment to improve the clinical efficacy ( 49 , 50 ).…”

Thyroid Carcinoma: Phenotypic Features, Underlying Biology and Potential Relevance for Targeting Therapy

“…The main pathways and mutations that are involved in thyroid oncogenesis are described as following. Since this section focuses on the most dominant pathways and mutations in thyroid cancer in general, we refer researchers who are interested in detailed PTC-specific genetic events about intratumoral heterogeneity to a review article by Fugazzola et al [ 58 ].…”