Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb 7;12(2):383.
doi: 10.3390/cancers12020383.

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

Laura Fugazzola  1 , Marina Muzza  1 , Gabriele Pogliaghi  1 , Mario Vitale  2
Affiliations
Review

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

Laura Fugazzola et al. Cancers (Basel). .

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.

Keywords: BRAF 3; RET/PTC; clonality; heterogeneity; thyroid cancer.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Hypotheses related to papillary thyroid cancer oncogenesis and progression (see text). (A) A known mutation occurs in the thyroid follicular cell and leads to the development of the tumor. (B,C) The tumor is established by a genetic driver (known or unknown). A second genetic event is acquired either in the same cell (B) or in a different cells (C) and transmitted with a sub-clonal distribution at the primary site. (D)A second genetic event is acquired at the metastatic site.
See this image and copyright information in PMC

References

    1. Burrell R.A., McGranahan N., Bartek J., Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–345. doi: 10.1038/nature12625. - DOI - PubMed
    1. Andor N., Graham T.A., Jansen M., Xia L.C., Aktipis C.A., Petritsch C., Ji H.P., Maley C.C. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat. Med. 2016;22:105–113. doi: 10.1038/nm.3984. - DOI - PMC - PubMed
    1. Raynaud F., Mina M., Tavernari D., Ciriello G. Pan-cancer inference of intra-tumor heterogeneity reveals associations with different forms of genomic instability. PLoS Genet. 2018;14:e1007669. doi: 10.1371/journal.pgen.1007669. - DOI - PMC - PubMed
    1. Bedard P.L., Hansen A.R., Ratain M.J., Siu L.L. Tumour heterogeneity in the clinic. Nature. 2013;501:355–364. doi: 10.1038/nature12627. - DOI - PMC - PubMed
    1. McGranahan N., Swanton C. Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell. 2017;168:613–628. doi: 10.1016/j.cell.2017.01.018. - DOI - PubMed