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Anaplastic Thyroid Carcinoma: Current Issues in Genomics and Therapeutics

Authors:
Ichiro Abe at Fukuoka University
Ichiro Abe
Alfred King-yin Lam at Griffith University
Alfred King-yin Lam
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Purpose of Review Anaplastic thyroid carcinoma is a type of thyroid carcinoma with the most aggressive biological behaviour amongst thyroid cancer. Here, we review the current genomic and the impacts of advances in therapies to improve the management of patients with the cancer. Recent Findings Common mutations being identified in anaplastic thyroid carcinoma are p53 and TERT promoter mutations. Other common mutated genes included BRAF, RAS, EIF1AX, PIK3CA, PTEN and AKT1, SWI/SNF, ALK and CDKN2A. Changes in expression of different microRNAs are also involved in the pathogenesis of anaplastic thyroid carcinoma. Curative resection combined with radiotherapy and combination chemotherapies (such as anthracyclines, platins and taxanes) has been shown to have effects in the treatment of some patients with anaplastic thyroid carcinoma. Newer molecular targeted therapies in clinical trials target mostly the cell membrane kinase and downstream proteins. These include targeting the EGFR, FGFR, VEGFR, c-kit, PDGFR and RET on the cell membrane as well as VEGF itself and the downstream targets such as BRAF, MEK and mTOR. Immunotherapy is also being tested in the cancer. Summary Updated knowledge of genomic as well as clinical trials on novel therapies is needed to improve the management of the patients with this aggressive cancer.
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HEAD AND NECK CANCERS (EY HANNA, SECTION EDITOR)
Anaplastic Thyroid Carcinoma: Current Issues
in Genomics and Therapeutics
Ichiro Abe
1,2
&Alfred King-yin Lam
1,3,4
Accepted: 11 January 2021
#The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Abstract
Purpose of Review Anaplastic thyroid carcinoma is a type of thyroid carcinoma with the most aggressive biological behaviour
amongst thyroid cancer. Here, we review the current genomic and the impacts of advances in therapies to improve the manage-
ment of patients with the cancer.
Recent Findings Common mutations being identified in anaplastic thyroid carcinoma are p53 and TERT promoter mutations.
Other common mutated genes included BRAF,RAS,EIF1AX,PIK3CA,PTEN and AKT1,SWI/SNF,ALK and CDKN2A.
Changes in expression of different microRNAs are also involved in the pathogenesis of anaplastic thyroid carcinoma.
Curative resection combined with radiotherapy and combination chemotherapies (such as anthracyclines, platins and taxanes)
has been shown to have effects in the treatment of some patients with anaplastic thyroid carcinoma. Newer molecular targeted
therapies in clinical trials target mostly the cell membrane kinase and downstream proteins. These include targeting the EGFR,
FGFR, VEGFR, c-kit, PDGFR and RET on the cell membrane as well as VEGF itself and the downstream targets such as BRAF,
MEK and mTOR. Immunotherapy is also being tested in the cancer.
Summary Updated knowledge of genomic as well as clinical trials on novel therapies is needed to improve the management of
the patients with this aggressive cancer.
Keywords Anaplastic thyroid carcinoma .Treatment .Genomics .BRAF .TERT
Introduction
Anaplastic thyroid carcinoma is one of the most lethal human
carcinomas [1]. The carcinoma responds very poorly to conven-
tional treatments. The recent development of next-generation
sequencing revealed more information about genetic profiles on
anaplastic thyroid carcinoma. The genomic of the carcinoma is
complex and difficult to be targeted in the current clinical prac-
tices. Nevertheless, these genomic data are useful for future ad-
vances in the treatment of anaplastic thyroid carcinoma. In this
article, we review the new development in genomics and the
application of these data to complement the advance of treatment
in patients with anaplastic thyroid carcinoma.
Genomic Changes in Anaplastic Thyroid
Carcinoma
Several next-generation sequencing studies have been per-
formed recently, including whole-genome sequencing studies
[2•], whole-exome sequencing studies [3,4] and targeted se-
quencing studies [5–14] to study the genetic changes in ana-
plastic thyroid carcinoma. The mainstream molecular mecha-
nism of anaplastic thyroid carcinoma is summarised in Fig. 1.
As anaplastic thyroid carcinoma is one of the most aggressive
human cancer, it follows that the genomics changes of ana-
plastic thyroid carcinoma are much complex and different
Ichiro Abe and Alfred King-yin Lam contributes equally as co-principal
authors
This article is part of the Topical Collection on Head and Neck Cancers
*Alfred King-yin Lam
a.lam@griffith.edu.au
1
Cancer Molecular Pathology, School of Medicine, Griffith
University, Gold Coast Campus, Gold Coast, QLD 4222, Australia
2
Department of Endocrinology and Diabetes Mellitus, Fukuoka
University Chikushi Hospital, Chikushino, Fukuoka 818-8502,
Japan
3
Faculty of Medicine, University of Queensland, Brisbane, Australia
4
Pathology Queensland, Gold Coast University Hospital, Southport,
QLD4215 Gold Coast, Australia
https://doi.org/10.1007/s11912-021-01019-9
/ Published online: 13 February 2021
Current Oncology Reports (2021) 23: 31
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Genetic profiling has identified several recurrent mutations that may prove useful in identifying novel targets. The most frequently identified mutations in ATC are TP53 and TERT promoter mutations [7][8][9], consistent with our findings, but these mutations are not associated with prognosis. On the other hand, the presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy [10]. ...
... On the other hand, the presence of a TP53 mutation was independently associated with reduced progression-free survival in BRAFV600E-mutated patients treated with BRAF-directed therapy [10]. BRAF mutations are common in ATC (7%-91%) [7,11], and in examination of a larger number of cases, this rate is about 50%. BRAF is a cytoplasmic serine-threonine protein kinase that plays a critical role in the MAPK signaling pathway. ...
Mutations in Anaplastic Thyroid Carcinoma: An Analysis of the Japanese National Genomic Database
Article
Full-text available
  • Mar 2025
Objectives The purpose of this study is to investigate the genetic mutational status of anaplastic thyroid carcinoma (ATC) and its prognostic implications. Methods Data were analyzed for 129 consecutive patients with ATC registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) between June 2019 and June 2024. Genetic alterations were determined by FoundationOne CDx or Liquid CDx next‐generation sequencing. The survival of patients was determined by the log‐rank test and a Cox proportional hazards model. Results The top 30 mutations in ATC were TERT (98/129), TP53 (88/129), BRAF (72/129), CDKN2A (39/129), CDKN2B (29/129), LTK (26/129), NRAS (25/129), KMT2D (24/129), PIK3CA (26/129), NOTCH3 (27/129), NF2 (19/129), MTAP (17/129), TET2 (16/129), STK11 (15/129), ATM (14/129), FANCA (14/129), NF1 (13/129), DNMT3A (13/129), KIT (13/129), NOTCH1 (13/129), EP300 (12/129), BRCA2 (11/129), CARD11 (11/129), KEL (11/129), MSH3 (11/129), PTEN (11/129), RICTOR (11/129), TSC1 (11/129), ROS1 (10/129), and KMT2A (10/129) with 13.7 ± 0.5 (mean ± SEM) mutations/individual. Mutations in BRAF (p = 0.003), PIK3CA (p = 0.014), and BRCA2 (p = 0.036) were associated with a significantly better prognosis, whereas mutations in STK11 (p = 0.024) was associated with a significantly worse prognosis, as determined by log‐rank tests. The hazard ratios for cases with these mutations were 0.248 (95% CI, 0.0973–0.633, p = 3.5 × 10⁻³) for PIK3CA, 2.410 (1.054–5.515, p = 0.037) for STK11, and 0.157 (0.0376–0.659, p = 0.011) for BRCA2. Conclusions In ATC, PIK3CA, and BRCA2 mutations were associated with a better prognosis, and STK11 mutation was associated with a poorer prognosis in this study. Level of Evidence 3.
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... The arrival of advanced genomic sequencing technologies has significantly expanded our understanding of the alterations that cooperate with driver mutations, playing essential roles in thyroid cancer progression and in some cases contribute to the development of deadly anaplastic thyroid carcinomas [14][15][16][17][18][19][20][21]. These alterations include TERT promoter mutations, loss-of-function mutations in tumor suppressor genes such as TP53, PTEN, and RBM10, gain of function mutations in PI3K pathway genes and EIF1AX, and mutations in genes involved in epigenetic regulation [7][8][9][22][23][24][25]. The initial generation of these combined transgenic mice (reviewed in [26,10, 27,21]), which included oncogenic Braf, Kras, and Hras knock-ins with the common cooperating alterations found in human genomic studies of advanced thyroid cancer (i.e., TERT promoter, TP53, PI3K pathway genes, EIF1AX), confirmed the ability of these cooperating mutations to promote tumor progression when combined with driver alterations. ...
Development of animal models to study aggressive thyroid cancers
Article
Full-text available
  • Jan 2025
The development of mouse models for thyroid cancer has significantly advanced over the years, enhancing our understanding of thyroid tumorigenesis, molecular pathways, and treatment responses. The earliest mouse models of thyroid cancer relied on hormone, radiation, or chemical carcinogenesis to induce tumors. However, as our understanding of the genetic alterations driving thyroid cancer has expanded, more sophisticated genetic engineering techniques have been employed to create models with thyroid-specific expression of these driver mutations. While driver mutations can initiate tumorigenesis, they are often insufficient to sustain cancer progression and invasion, which significantly limits their usefulness in studying advanced thyroid cancers. Recent studies exploring the genomic landscape of advanced thyroid cancer have identified several cooperating mutations, which are secondary genetic alterations that work alongside driver mutations to promote thyroid tumor progression. Indeed, mice with a combination of oncogenic drivers and common cooperating alterations have been developed, demonstrating that these alterations function in conjunction with the oncogenic driver to promote the progression to advanced thyroid cancer. These models provide important preclinical tools to explore how cooperating alterations influence the response to therapies, particularly those targeting the oncogenic driver. This review will focus on recent publications that broaden the scope of advanced thyroid cancer models by combining thyroid-specific oncogenic driver expression with various cooperating mutations.
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... In addition, in vivo studies showed that the PD-L1 antibody effectively suppresses tumor growth in cases of ATC with PD-L1 expression. 27,28 A study conducted immune scoring on 505 patients with thyroid cancer, and the results showed that the degree of differentiation of thyroid cancer was significantly negatively correlated with immunosuppressive markers CTLA-4 and PD-L1. Compared with wild-type tumors, these immunosuppressive markers were more frequently found in BRAF V600E-mutated tumors. ...
Advanced anaplastic thyroid carcinoma with positive expression of PD-L1 response to immune checkpoint inhibitors: A case report
Article
Full-text available
  • Jan 2025
Anaplastic thyroid carcinoma (ATC) is one rare type of thyroid carcinoma without standard systemic treatment for advanced disease. Recent evidence has demonstrated promising efficacy of immune checkpoint inhibitors, particularly those targeting programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1), in a variety of solid tumors. However, there have been no research of immune checkpoint inhibitors plus chemotherapy in ATC. Here, we present the case of a 37-year-old man with metastatic ATC with positive PD-L1 expression, who achieved long-term remission of 34 months after later-line treatment with zimberelimab (a PD-1 inhibitor) and nab-paclitaxel, followed by single-agent zimberelimab maintenance therapy. After three cycles of the combination treatment, the thyroid lesion and the liver metastases shrank dramatically, leading to the best overall response of partial remission. PD-L1 expression may serve as a potential biomarker for tumor response to immune checkpoint inhibitors in ATC. Our review highlights the need for further studies investigating the role of PD-L1 status as biomarker to predict the prognosis of immunotherapy in the treatment of ATC.
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... PTEN (phosphatase and tensin homolog) encoded PTEN enzyme, which acts as a tumor suppressor by regulating cell division and preventing abnormal cell growth and division. 35 mTOR is a regulatory protein, involved in the PI3K/Akt/ mTOR pathway, which increases the uptake of iodine from thyroid cells to promote cell proliferation and survival. Genetic alterations occurring in this pathway play a role in the progression of ATC. ...
Benzyl isothiocyanate suppresses development of thyroid carcinoma by regulating both autophagy and apoptosis pathway
Article
Full-text available
  • Aug 2024
Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, characterized by rapid growth and invasion and poor prognosis. Due to its rarity and aggressive nature, ATC is a difficult condition to treat, thus knowledge of the mechanisms underlying its progression represents important research challenges. Benzyl isothiocyanate (BITC) is a natural compound that has shown promising anticancer properties. The aim of this study was to evaluate the antitumor effect of BITC in ATC, highlighting signaling pathways involved in BITC mechanism of action. This work included in vitro and in vivo studies. Results obtained indicate that BITC, both in vitro and in vivo, has the potential to slow the progression of ATC through interactions with autophagy, reduction in epithelial-mesenchymal transition (EMT) and attenuation of inflammation. In conclusion, this study identifies BITC as a compound worth further investigation for the development of new treatment strategies for this aggressive form of thyroid cancer.
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... For locally advanced differentiated and medullary thyroid cancers, systemic treatments predominantly involve targeted therapies [2][3][4] aimed at inhibiting angiogenesis and tumor progression, thereby delaying disease advancement. In contrast, undifferentiated (anaplastic) thyroid cancers, characterized by their aggressive nature, necessitate a comprehensive treatment approach combining surgery, radiotherapy, chemotherapy, and targeted therapy [5,6]. A significant challenge in the long-term management of these cancers is the development of resistance to targeted therapeutic agents [7][8][9]. ...
Appraising the effectiveness of immune cells on thyroid cancer: a Mendelian randomization study
Article
Full-text available
  • Jul 2024
  • ENDOCRINE
Background The intricate interplay between the immune system and tumor plays a pivotal role in thyroid cancer (TC) pathogenesis, potentially influencing both the causation and therapeutic outcomes. Despite extensive research, existing literature offers ambiguous insights regarding the association between immune cell traits and thyroid cancer progression. Methods To elucidate the potential causal relationships, we conducted an integrated two-sample Mendelian randomization (MR) analysis. This study utilized publicly genetic datasets to explore the causalities between 731 immune cell traits (categorized into four trait types across seven panels) and thyroid cancer. We ensured the robustness of our findings through comprehensive sensitivity analyses, meticulously assessing potential sources of bias such as pleiotropy. Results After False Discovery Rate (FDR) correction, six immune cell traits were identified to be significantly associated with thyroid cancer risk (Inverse Variance Weighted, IVW): Absolute count of gamma delta T cells/ T-cell receptor gamma delta absolute count (TCRgd AC) 0.8464 (OR95% CI = 0.7477-0.9580, P = 0.0083, PFDR = 0.0103); CD8 on bright CD8 cells (CD8 on CD8br) 0.8867 (OR95% CI = 0.8159-0.9637, P = 0.0047, PFDR = 0.0093); CD127 on CD45RA negative CD4 T cells not regulatory T cells (CD127 on CD45RA- CD4 not Treg) 0.8969 (OR95% CI = 0.8192-0.9820, P = 0.0186, PFDR = 0.0186); CD80 on CD62L positive plasmacytoid dendritic cells (CD80 on CD62L+ plasmacytoid DC) 1.1091 (OR95% CI = 1.0267-1.1982, P = 0.0086, PFDR = 0.0103); CD80 on plasmacytoid DC 1.1283 (OR95% CI = 1.0462-1.2168, P = 0.0017, PFDR = 0.0093); Side scatter-area on bright CD8 cells (SSC − A on CD8br) 1.1622 (OR95% CI = 1.0507-1.2854, P = 0.0035, PFDR = 0.0093). Conclusions Our study demonstrated the causalities between immune cell traits and thyroid cancers by Mendelian randomization study, thus guiding future mechanism studies.
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... Differentiated TC (DTC) derives from thyroid follicular cells and is represented by follicular TC (FTC) and papillary TC (PTC) for~85-95% of TCs. Hürthle cells TC and poorly differentiated TC (PDTC) represent~2-5% and anaplastic TC (ATC) ALK fusions are considered both a diagnostic marker and a possible therapeutic target, as shown by different case reports of patients with ALK-positive TC, including cases of metastatic and RAI-resistant cancer treated with crizotinib [45][46][47]. ...
Antineoplastic Effect of ALK Inhibitor Crizotinib in Primary Human Anaplastic Thyroid Cancer Cells with STRN–ALK Fusion In Vitro
Article
Full-text available
Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in “primary human ATC cells” (pATCs) with transforming striatin (STRN)–ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN–ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN–ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN–ALK), particularly in those with STRN–ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN–ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients.
View
State of Knowledge About Thyroid Cancers in the Era of COVID-19—A Narrative Review
Article
Full-text available
  • Dec 2024
Thyroid cancer (TC), due to its heterogeneous nature, remains a clinical challenge. Many factors can initiate the carcinogenesis process of various types of TC, which complicates diagnosis and treatment. The presented review gathers current information on specific types of TC, taking into account the effects of the COVID-19 pandemic. It is likely that COVID-19 has influenced and continues to influence the function of the thyroid gland. A high percentage of patients with COVID-19 showing simultaneous pathological changes in the thyroid suggests that SARS-CoV-2 may disrupt the function of this gland and initiate pro-oxidative mechanisms, inflammatory states, and autoimmune diseases, thereby promoting the formation of neoplastic changes. Furthermore, changes in the expression of the ACE2, TMPRSS2, CLEC4M and DPP4 genes, observed in TC, also occur in COVID-19. Therefore, it is probable that the interaction of SARS-CoV-2 with thyroid cell receptors may initiate carcinogenesis in this gland. Additionally, some drugs used in TC therapy (e.g., levothyroxine) may increase the affinity of SARS-CoV-2 for cells, which could contribute to a more severe course of COVID-19 and the emergence of long-term symptoms (post-COVID-19). Moreover, the consequences of sanitary restrictions (limited access to medical services, reduction in endocrinological and oncological procedures) that took place in many countries during the COVID-19 pandemic may lead in the future to an increased number of missed diagnoses and the emergence of aggressive cancers.
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iPLA 2 β regulates the dual effects of arachidonic acid in thyroid cancer
Article
  • Sep 2024
Background Abnormal arachidonic acid metabolism in the tumor microenvironment is closely related to cancer progression; however, thyroid cancer was rarely researched. Methods Through lipidomic analysis, we disclosed that dysregulated arachidonic acid metabolism plays dual effects on thyroid cancer. The promoting role of arachidonic acid in the progression of thyroid cancer cells was evaluated utilizing cell viability (CCK‐8 assay) and transwell invasion assays, confirmed by corresponding inhibitors. Lipid peroxidation and the use of various cell death inhibitors confirmed that arachidonic acid confers vulnerability to ferroptosis in thyroid cancer. The roles of arachidonic acid and ferroptosis inducer in thyroid cancer were assessed in a xenograft mouse model. Results On one hand, arachidonic acid promotes the progression of thyroid cancer through the cyclooxygenase/prostaglandin pathway; on another hand, arachidonic acid confers vulnerability to ferroptosis through lipoxygenases. Moreover, iPLA2β drives converse roles of arachidonic acid between cancer‐progression and ferroptosis vulnerability through releasing free arachidonic acid from the cell membrane. Finally, we confirmed high arachidonic acid diet promotes the development of thyroid cancer in vivo, whereas ferroptosis inducer sulfasalazine dramatically reduced tumor growth of mice with feeding arachidonic acid. Conclusions Our research demonstrated the roles of iPLA2β in conversing dual effects of arachidonic acid in thyroid cancer and provides ferroptosis inducer as a potential therapeutic strategy.
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C5AR1-induced TLR1/2 pathway activation drives proliferation and metastasis in anaplastic thyroid cancer
Article
  • Jun 2024
  • MOL CARCINOGEN
This study aimed to elucidate the role and mechanisms of Complement C5a receptor 1 (C5AR1) in driving the malignant progression of anaplastic thyroid carcinoma (ATC). C5AR1 expression was assessed in ATC tissues and cell lines. Functional assays evaluated the effects of C5AR1 knockdown on the malignant features of ATC cells. The interaction between C5AR1 and miR‐335‐5p was confirmed using a luciferase reporter assay and Fluorescence in situ hybridization, and the impact of C5AR1 knockdown on the Toll‐like receptor (TLR) 1/2 signaling pathway was examined. In vivo studies evaluated the effects of C5AR1 modulation on tumor growth and metastasis. C5AR1 levels were elevated in ATC tumor samples and associated with poor survival in ATC patients. C5AR1 knockdown impeded ATC cell proliferation, migration, and invasion in vitro. MiR‐335‐5p was identified as an upstream regulator of C5AR1, which negatively modulates C5AR1 expression. C5AR1 knockdown diminished TLR1, TLR2, and myeloid differentiation primary response 88 (MyD88) levels, while C5AR1 overexpression activated this pathway. Blocking TLR1/2 signaling abrogated the oncogenic effects of C5AR1 overexpression. C5AR1 silencing inhibited tumor growth and lung metastasis of ATC cells in nude mice. C5AR1 contributes to ATC tumorigenesis and metastasis by activating the TLR1/2 pathway, and is negatively regulated by miR‐335‐5p. Targeting the miR‐335‐5p/C5AR1/TLR1/2 axis represents a potential therapeutic strategy for ATC.
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Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma
Article
Full-text available
  • May 2020
With the understanding of the complex interaction between the tumour microenvironment and immunotherapy, there is increasing interest in the role of immune regulators in the treatment of head and neck squamous cell carcinoma (HNSCC). Activation of T cells and immune checkpoint molecules is important for the immune response to cancers. Immune checkpoint molecules include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1), T-cell immunoglobulin mucin protein 3 (TIM-3), lymphocyte activation gene 3 (LAG-3), T cell immunoglobin and immunoreceptor tyrosine-based inhibitory motif (TIGIT), glucocorticoid-induced tumour necrosis factor receptor (GITR) and V-domain Ig suppressor of T cell activation (VISTA). Many clinical trials using checkpoint inhibitors, as both monotherapies and combination therapies, have been initiated targeting these immune checkpoint molecules. This review summarizes the functional mechanism and use of various immune checkpoint molecules in HNSCC, including monotherapies and combination therapies, and provides better treatment options for patients with HNSCC.
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Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma
Article
Full-text available
  • Apr 2020
Background: Anaplastic thyroid carcinoma (ATC) remains one of the most challenging malignancies to treat in the modern era. Most patients present with or develop recurrent/metastatic incurable disease with poor response rates to conventional chemotherapy, and life expectancy is short. Next generation sequencing (NGS) can be leveraged in ATC to identify oncogenic alterations that can be targeted with molecularly specific therapy, offering new, effective treatment options to a subset of patients. Patient findings: A 73-year-old man presenting with locally advanced papillary thyroid carcinoma containing a minor component of ATC was treated with surgery and iodine-131. He developed biopsy-confirmed ATC distant metastases that progressed on cytotoxic chemotherapy. NGS revealed several alterations, including a CCDC6-RET gene fusion. The patient enrolled in LIBRETTO-001, a phase I/II trial of the potent and specific RET inhibitor, LOXO-292. The patient tolerated LOXO-292 well and experienced a deep and durable partial response, ongoing beyond 14 months. Conclusion: This clinically significant response achieved with LOXO-292 in a patient with a CCDC6-RET fusion-positive ATC who had exhausted conventional treatment options highlights the importance of conducting tumor genomic profiling in patients with ATC to identify uncommon but actionable genomic alterations, such as RET gene fusions.
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miR‐338‐5p reverses chemoresistance and inhibits invasion of esophageal squamous cell carcinoma cells via targeting Id‐1
Article
Full-text available
5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used to treat esophageal squamous cell carcinoma (ESCC), but acquisition of chemoresistance frequently occurs and the underlying mechanisms are not fully understood. We found that miR-338-5p was underexpressed in ESCC cells with acquired 5-FU chemoresistance. Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment. The effects were abolished by re-expression of Id-1. On the other hand, miR-338-5p-knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, while knockdown of both miR-338-5p and Id-1 re-sensitized the cells to 5-FU. In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells. Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'UTR of Id-1. We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC. Notably, low serum miR-338-5p expression level was associated with poorer survival and poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy. In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p may be a novel non-invasive prognostic and predictive biomarker in ESCC.
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Sorafenib inhibits vascular endothelial cell proliferation stimulated by anaplastic thyroid cancer cells regardless of BRAF mutation status
Article
Full-text available
  • Sep 2019
Anaplastic thyroid cancer (ATC) is a rare refractory disease, frequently associated with BRAF mutations and aberrant vascular endothelial growth factor (VEGF) secretion. The antitumor effects of sorafenib were evaluated, and its mechanisms of action were investigated. Four human ATC cell lines were used: OCUT‑4, which possesses a BRAF mutation; OCUT‑6 and ACT‑1, which carry NRAS mutations; and OCUT‑2, which possesses mutations in BRAF and PI3KCA. The viability of Sorafenib was evaluated by MTT assay. In order to examine the inhibitory effect of Sorafenib on intracellular signal transduction, expression of mitogen‑activated protein kinase kinase was examined by western blotting. In addition, cell cycle analysis was performed using flow cytometry. The inhibitory effects of sorafenib on the growth of ATC cells and human umbilical vein endothelial cells (HUVECs) stimulated with conditioned media from ATC cells were examined. Sorafenib inhibited the viability of OCUT‑4 more effectively than other ATC cell lines; these effects may have been mediated cytostatically by suppressing mitogen‑activated protein kinase kinase phosphorylation. Conversely, similar suppression was not observed in OCUT‑6 cells, which possess an NRAS mutation. The four cell lines secreted different quantities of VEGF, and the proliferation of HUVECs was differentially stimulated by their conditioned media. Both anti‑VEGF antibody and sorafenib prevented this stimulation of proliferation. In conclusion, sorafenib more effectively inhibited RAF‑generated growth signals in ATC cells compared with signals generated by its upstream gene, RAS. ATC cells stimulated the growth of HUVECs via humoral factors, including VEGF; this effect was clearly inhibited by sorafenib. The present findings highlighted the potential of sorafenib for the treatment of ATC and provided insight into its mechanism of action.
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Spectrum of TERT promoter mutations and mechanisms of activation in thyroid cancer
Article
Full-text available
  • Aug 2019
Background: Reactivation of telomerase reverse transcriptase (TERT) is an important event in cancer. Two hotspot mutations in the TERT promoter region, c.-124C > T (C228T) and c.-146C > T (C250T), occur in various cancer types including thyroid cancer. They generate de novo binding sites for E-twenty-six (ETS) transcription factors causing increased TERT transcription. The aim of this study was to search for novel TERT promoter mutations and additional mechanisms of TERT activation in thyroid cancer. Methods: We studied 198 papillary thyroid carcinomas (PTCs), 34 follicular thyroid carcinomas (FTCs), 40 Hürthle cell carcinomas (HCCs), 14 poorly differentiated/anaplastic thyroid carcinomas (PDTC/ATC), and 15 medullary thyroid carcinomas (MTCs) for mutations in an -424 bp to +64 bp region of TERT. The luciferase reporter assay was used to functionally characterize the identified alterations. Copy number variations (CNVs) in the TERT region were analyzed using TaqMan copy number assay and validated with fluorescence in situ hybridization (FISH). Results: We detected the hotspot c.-124C > T and c.-146C > T mutations in 7% PTC, 18% FTC, 25% HCC, and 86% PDTC/ATC. One PTC carried a c.-124C > A mutation. Furthermore, we identified two novel mutations resulting in the formation of de novo ETS-binding motifs: c.-332C > T in one MTC and c.-104_-83dup in one PTC. These genetic alterations, as well as other detected mutations, led to a significant increase in TERT promoter activity when assayed using luciferase reporter system. In addition, 5% of thyroid tumors were found to have ≥3 copies of TERT. Conclusions: This study confirms the increased prevalence of TERT promoter mutations and CNV in advanced thyroid cancers and describes novel functional alterations in the TERT gene promoter, including a point mutation and small duplication. These mutations, as well as TERT copy number alterations, may represent an additional mechanism of TERT activation in thyroid cancer.
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Immunohistochemistry for Protein Detection in Esophageal Squamous Cell Carcinoma
Chapter
  • Feb 2020
Immunohistochemistry is the identification of a cell protein by a specific antibody targeting that protein. It is the most common ancillary test to study the pathology of cancer. Immunohistochemical protein markers are used to differentiate poorly differentiated squamous cell carcinoma from poorly differentiated adenocarcinoma or neuroendocrine carcinomas. They could be used to identify and type the carcinoma in metastatic locations. Importantly, immunodetection of markers also helps in prediction of response to therapies as well as assessing the different biomarkers related to the pathogenesis and clinical behavior of esophageal squamous cell carcinoma. Successful application of the immunochemistry depends on understanding the mechanisms and principles as well as the limitations of the procedure. Automation of the procedure by different models of automatic stainers is widely used in diagnostic laboratories. The use of autostainers streamlines the workflows and certainly reduces the labor, time, and cost of using immunohistochemistry in clinical and research settings.
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Roles of MicroRNAs in Esophageal Squamous Cell Carcinoma Pathogenesis
Chapter
  • Feb 2020
MicroRNAs (miRNAs) are 20–22 nucleotides long single-stranded noncoding RNAs. They regulate gene expression posttranscriptionally by base pairing with the complementary sequences in the 3′-untranslated region of their targeted mRNA. Aberrant expression of miRNAs leads to alterations in the expression of oncogenes and tumor suppressors, thereby affecting cellular growth, proliferation, apoptosis, motility, and invasion capacity of gastrointestinal cells, including cells of esophageal squamous cell carcinoma (ESCC). Thus, alterations in miRNAs expression associated with the pathogenesis and progression of ESCC. In addition, expression profiles of miRNAs correlated with various clinicopathological factors, including pathological stages, histological differentiation, invasion, metastasis of cancer, as well as survival rates and therapy response of patients with ESCC. Consequently, expression profiles of miRNAs could be useful as diagnostic, prognostic, and prediction biomarkers in ESCC. Herein, we describe the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and microarray methods for detection and quantitate miRNAs in ESCC. In addition, we summarize the roles of miRNAs in ESCC pathogenesis, progression, and prognosis.
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PIK3CA mutation and clinicopathological features of colorectal cancer: a systematic review and Meta-Analysis
Article
  • Sep 2019
Background: There is conflicting evidence regarding the association between PIK3CA mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between PIK3CA mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of PIK3CA mutations in CRC. Materials and Methods: A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between PIK3CA mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of PIK3CA mutations on outcome parameters. Results: Forty-four studies enrolling 17621 patients were eligible for inclusion. PIK3CA mutations were associated with proximal tumor location, mucinous differentiation, KRAS mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that PIK3CA exon 9 mutations were positively associated with proximal tumor location and KRAS mutations, and negatively associated with BRAF mutations and MSI; exon 20 mutations were associated with proximal tumor location, KRAS mutations, BRAF mutations and MSI. Conclusions: Our findings suggest that overall or exon-specific PIK3CA mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC. As PIK3CA mutations were found to be closely associated with KRAS mutations, their relationship warrants further investigation. Since PIK3CA exon 9 and 20 mutations showed different tendencies with regard to BRAF mutation and MSI status, they may have distinct molecular impacts on CRC.
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