Anaplastic thyroid cancer – an overview of genetic variations and treatment modalities

Abstract

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive malignancy that accounts for about 1%-2% of all thyroid cancer diagnoses but is responsible for up to 30%-40% of thyroid cancer deaths. ATCs are poorly differentiated tumors that develop on the background of preexisting, often undiagnosed, papillary thyroid carcinoma or follicular thyroid carcinoma, through progressive accumulation of changes in several oncogenic and tumor suppressor pathways, including p53, RAS, RAF, Wnt-β-catenin and the PTEN-AKT pathways. Consequently, the 1-year survival rate after diagnosis ranges from 5% to 15%. Current therapeutic approaches are aimed at common late oncogenic changes and involve inhibition of MAPK and PI3K cell proliferation pathways or restoration of p53 and PTEN tumor suppressor pathways. Since singlemodality therapy has limited effect on anaplastic thyroid cancer, aggressive multimodal treatments are now the treatment of choice, in spite of which, the mean survival time from diagnosis to death continues to remain at about 6 months. The current review attempts to summarize the genetics involved in the development and progression of ATC and provides some insight into the therapeutic options being evaluated for this aggressive cancer.

REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway

“…ATC has the most aggressive progression among thyroid malignancies due to its dedifferentiation; however, the molecular mechanisms of ATC are far from understood. Mutations of various pathways, including p53, Braf, Ras, PTEN/PI3K, and Wnt-β-catenin have been described as potential drivers for ATC [23]. Current therapeutic approaches commonly aim at inhibiting cell proliferation pathways or restoring the function of tumor suppressors.…”

“…However, single-modality therapy such as Braf inhibitor, PI3K inhibitor, or multimodal treatments has limited effects on ATC, and the mean survival time from diagnosis to death continues to remain at about 6 months [23]. Therefore, there is an urgent need for novel therapies against ATC.…”

An Overview on Prevalence and Detection Approaches of BRAF V600E Mutation in Anaplastic Thyroid Carcinoma: A Systematic Review and Meta-Analysis

“…Besides, additional alterations in several pathways, including the Wnt-β-catenin, the PTEN-AKT, the PI3/AKT/mTOR pathways, and mutations in the SWI/SNF complex, AID/APOBEC family of cytidine deaminases, histone modification genes, cell cycle genes and loss of function mutations in DNA repair genes have been reported in ATC ( 10 – 14 ). Acquisition of various genetic aberrations in the multi-step progression of ATC causes high rates of metastasis and mortalities, resistance to RAI and conventional therapies, so understanding the genetics involved in the process of development of ATC provides identifying novel targeted therapies and methods for therapeutic options in ATC patients ( 2 , 15 , 16 ).…”

Androgen Receptor Activation Induces Senescence in Thyroid Cancer Cells

“…Other genes that are altered in thyroid cancers include TP53, IDH1, CTNNB1, and NDUFA13. TP53 encodes the tumor suppressor p53, and its perturbation is observed in 80% of ATC cases [ 11 ]. ATC has river mutations similar to PTC, such as BRAF, but also contains additional alterations, including TERT, TP53, NRAS, CDK4, APC, MED12, ERBB2, DIVER1, AR1D1A, and MEN1 [ 12 ].…”