Immunohistochemical and Sequencing Analyses of the Wnt Signaling Components in Japanese Anaplastic Thyroid Cancers

Kurihara, Toshio; Ikeda, Satoshi; Ishizaki, Yasuyo; Fujimori, Masahiko; Tokumoto, Noriaki; Hirata, Yuzoh; Ozaki, Shinji; Okajima, Masazumi; Sato, Keizo; Asahara, Toshimasa

doi:10.1089/thy.2004.14.1020

Cited by 50 publications

(38 citation statements)

References 42 publications

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“…Ninetystudies and in early human clinical trials (6,7). These efforts are constrained by the paucity of information on the genomics of these cancers, which have been investigated primarily through Sanger sequencing of a limited set of candidate genes (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). The exception to this is a recently reported whole exome sequencing study of ATC (21), which, although informative, may have undercalled significant mutations -particularly those that are subclonal -because of low tumor purity.…”

Section: Somatic Mutationsmentioning

confidence: 99%

“…Table 6 for detailed clinical correlations. Mutations of genes encoding members of the WNT signaling pathway -i.e., CTNNB1 (β catenin), AXIN1, and APC -have previously been reported as genetic hallmarks of ATCs (12,13), with mutation frequencies >60% for CTNNB1 (reviewed in Supplemental Table 8). The deep-sequencing results in our cohort do not replicate these findings.…”

Section: Somatic Mutationsmentioning

confidence: 99%

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Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Landa¹,

Ibrahimpašić²,

Boucai³

et al. 2016

Journal of Clinical Investigation

978

1,212

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IntroductionA comprehensive investigation of the genomic landscape of papillary thyroid carcinomas (PTC), the most common thyroid malignancy, was recently reported by The Cancer Genome Atlas Network (TCGA Network) (1). These well-differentiated tumors were found to have a low frequency of somatic alterations (2), with the majority harboring mutually exclusive activating mutations in BRAF (60%) and RAS-family genes (13%), as well as fusion oncoproteins, primarily involving receptor tyrosine kinases (RTKs) such as RET, NTRK1 or -3, and ALK. Distinct signaling and transcriptomic consequences were observed between BRAF V600E -like tumors, which showed higher MAPK transcriptional output and lower expression of genes involved in iodine metabolism, and RAS-like tumors, which had lower MAPK signaling and comparatively preserved expression of iodine-related genes.The TCGA study excluded poorly differentiated thryoid cancers (PDTCs) and anaplastic thyroid cancers (ATCs) from their analysis in order to focus on a homogeneous histological cohort that would provide sufficient power to identify low-frequency genomic events. Although PDTCs and ATCs account for approximately 5%-10% of thyroid cancers, they represent a major clinical challenge. Patients with PDTC and ATC have a mean survival after diagnosis of 3.2 and 0.5 years, respectively, and account for approximately a third of deaths caused by this disease (3). Virtually all cases are refractory to radioiodine therapy, and traditional chemotherapy and radiotherapy are of marginal benefit (4, 5).Molecularly targeted approaches are being tested in preclinical BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization. METHODS.We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC). RESULTS.Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs w...

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Section: Somatic Mutationsmentioning

confidence: 99%

Section: Somatic Mutationsmentioning

confidence: 99%

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Landa¹,

Ibrahimpašić²,

Boucai³

et al. 2016

Journal of Clinical Investigation

978

1,212

View full text Add to dashboard Cite

show abstract

“…Alterations of the Wnt pathway are associated with hepatocellular carcinoma [21], and anaplastic carcinoma of the thyroid gland [22]. b-catenin mutations occur in medulloblastomas, hepatoblastomas and Wilm's tumours [23].…”

Section: Wnt Pathway and Cancermentioning

confidence: 99%

Common critical pathways in embryogenesis and cancer

2006

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“…Inappropriate activation of this pathway is considered to be the initiating event in transformation of intestinal epithelial cells [6]. In addition, it is commonly affected by mutation in many other cancers such as breast cancer, melanoma, hepatocellular carcinoma, pilomatricoma, medulloblastoma, prostate cancer, Wilm's tumor and ovarian cancer [7][8][9][10]. However, it is unclear what role of Wnt/b-catenin signal pathway plays in the development and progression of human gliomas.…”

Section: Introductionmentioning

confidence: 99%

Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations

et al. 2010

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Gliomas are the most common primary intracranial tumors. Understanding the molecular basis of gliomas' progression is required to develop more effective therapies. The Wnt/β-catenin signaling cascade is an important signal transduction pathway in human cancers. Although, overactivation of this pathway is a hallmark of several forms of cancer, little is known about its role in human gliomas. Here, we aimed to determine the clinical significance of Wnt/β-catenin pathway components in gliomas. Immunohistochemical staining was performed to detect the expression patterns of Wnt1, β-catenin and Cyclin D1 in the biopsies from 96 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyses were performed to evaluate the prognosis of patients. Cytoplasmic staining pattern of Wnt1, membranous, cytoplasmic and nuclear accumulation of β-catenin, and nuclear localization of Cyclin D1 were demonstrated by immunohistochemical staining. The Wnt1 expression significantly correlated with the expression of Cyclin D1 (P < 0.0001). The ratio of tumors with a cytoplasmic-nuclear pattern or a cytoplasmic pattern of β-catenin was significantly higher in Wnt1-positive (P < 0.01) and Cyclin D1-positive (P < 0.01) tumors than in Wnt1-negative and Cyclin D1-negative tumors, respectively. The protein expression levels of Wnt1, β-catenin and Cyclin D1 were all positively correlated with the Karnofsky performance scale (KPS) score and World Health Organization (WHO) grades of patients with gliomas. Furthermore, Wnt1, cytoplasmic-nuclear β-catenin and Cyclin D1 status were all the independent prognostic factors for glioma patients (P = 0.01, 0.007 and 0.005, respectively). These results provide convincing evidence that the Wnt/β-catenin pathway correlated closely with the progression of gliomas and might be a novel prognostic marker for this neoplasm.

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Immunohistochemical and Sequencing Analyses of the Wnt Signaling Components in Japanese Anaplastic Thyroid Cancers

Cited by 50 publications

References 42 publications

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers

Common critical pathways in embryogenesis and cancer

Wnt/beta-Catenin pathway in human glioma: expression pattern and clinical/prognostic correlations

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