PAX8; paired box 8 (2q13)

Gene Summary

Gene:PAX8; paired box 8
Summary:This gene encodes a member of the paired box (PAX) family of transcription factors. Members of this gene family typically encode proteins that contain a paired box domain, an octapeptide, and a paired-type homeodomain. This nuclear protein is involved in thyroid follicular cell development and expression of thyroid-specific genes. Mutations in this gene have been associated with thyroid dysgenesis, thyroid follicular carcinomas and atypical follicular thyroid adenomas. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:paired box protein Pax-8
Updated:14 December, 2014


What does this gene/protein do?
Show (45)

Cancer Overview

Research Indicators

Publications Per Year (1989-2014)
Graph generated 14 December 2014 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Oncogene Fusion Proteins
  • Neoplastic Cell Transformation
  • p53 Protein
  • Proto-Oncogene Proteins c-ret
  • Promoter Regions
  • Papillary Carcinoma
  • PAX8
  • FISH
  • Follicular Adenocarcinoma
  • Immunohistochemistry
  • Translocation
  • Thyroid Cancer
  • DNA Mutational Analysis
  • Transcriptional Activation
  • Thyroid Gland
  • Gene Expression Profiling
  • RAS Genes
  • DNA-Binding Proteins
  • Carcinoma, Papillary, Follicular
  • BRAF
  • Cancer Gene Expression Regulation
  • WT1
  • ras Proteins
  • Carcinoma
  • Messenger RNA
  • Receptors, Cytoplasmic and Nuclear
  • Paired Box Transcription Factors
  • Mutation
  • Nuclear Proteins
  • Base Sequence
  • Cell Differentiation
  • Adenoma
  • Young Adult
  • Gene Rearrangement
  • Biopsy, Fine-Needle
  • Chromosome 2
  • Transcription Factors
  • Kidney Cancer
  • Point Mutation
Tag cloud generated 14 December, 2014 using data from PubMed, MeSH and CancerIndex

Notable (2)

Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Thyroid CancerPAX8-PPARG fusion in Folicular Thyroid Cancer
PAX8-PPARG fusion is present in follicular thyroid cancer (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA).
View Publications72
Kidney CancerPAX8 and Kidney Cancer View Publications59

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Related Links

Latest Publications: PAX8 (cancer-related)

Giordano TJ, Beaudenon-Huibregtse S, Shinde R, et al.
Molecular testing for oncogenic gene mutations in thyroid lesions: a case-control validation study in 413 postsurgical specimens.
Hum Pathol. 2014; 45(7):1339-47 [PubMed] Related Publications
Molecular testing for oncogenic gene alterations provides clinically actionable information essential for the optimal management of follicular cell thyroid cancer. We aimed to establish the distribution and frequency of common oncogenic gene mutations and chromosomal rearrangements in a comprehensive set of benign and malignant thyroid lesions. A case-control study was conducted in 413 surgical cases comprising 17 distinct histopathologic categories, 244 malignant, 169 benign, and 304 double-blinded specimens. Seventeen alterations of BRAF, HRAS, KRAS, NRAS, PAX8, and RET genes were evaluated using a single validated technology platform. Following verification of analytical sensitivity, accuracy, and precision in model and surgical specimens, 152 molecular positive results were generated in lesions representing multiple stages of progression and epithelial differentiation as well as rare subtypes of primary, secondary, or recurring tumors. Single mutations were found in 58% of primary malignant lesions and 12% of benign (P < .001). In the blinded validation set, mutation distribution and frequency were distinct across variants of follicular and papillary carcinomas. BRAF or RET-PTC was detected exclusively in malignant lesions but not in follicular carcinomas (P < .001). RAS or PAX8-PPARG were present in 23% of adenomas, and NRAS was found in a single nonneoplastic lesion (P = .0014). These data substantiate the diagnostic utility of molecular testing for oncogenic mutations and validate its performance in a variety of surgical specimens. Standardized and validated multianalyte molecular panels can complement the preoperative and postoperative assessment of thyroid nodules and support a growing number of clinical and translational applications with potential diagnostic, prognostic, or theranostic utility.

Related: Thyroid Cancer

Kanteti R, El-Hashani E, Dhanasingh I, et al.
Role of PAX8 in the regulation of MET and RON receptor tyrosine kinases in non-small cell lung cancer.
BMC Cancer. 2014; 14:185 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Non-small cell lung cancers (NSCLC) are highly heterogeneous at the molecular level and comprise 75% of all lung tumors. We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis. Subsequent studies from our lab also revealed that PAX5 transcription factor is preferentially expressed in small cell lung cancer (SCLC) and promotes MET transcription. PAX8, however, is also expressed in NSCLC cell lines. We therefore investigated the role of PAX8 in NSCLC.
METHODS: Using IHC analysis, PAX8 protein expression was determined in archival NSCLC tumor tissues (n = 254). In order to study the effects of PAX8 knockdown on NSCLC cellular functions such as apoptosis and motility, siRNA against PAX8 was used. Confocal fluorescence microscopy was used to monitor the localization of MET, RON and PAX8. The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay.
RESULTS: Relative levels of PAX8 protein were elevated (≥ + 2 on a scale of 0-3) in adenocarcinoma (58/94), large cell carcinoma (50/85), squamous cell carcinoma (28/47), and metastatic NSCLC (17/28; lymph node). Utilizing early progenitors isolated from NSCLC cell lines and fresh tumor tissues, we observed robust overexpression of PAX8, MET, and RON. PAX8 knockdown A549 cells revealed abrogated PAX8 expression with a concomitant loss in MET and the related RON kinase expression. A dramatic colocalization between the active form of MET (also RON) and PAX8 upon challenging A549 cells with HGF was visualized. A similar colocalization of MET and EGL5 (PAX8 ortholog) proteins was found in embryos of C. elegans. Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target. However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability.
CONCLUSION: PAX8 provides signals for growth and motility of NSCLC cells and is necessary for MET and RON expression. Further investigations are necessary to investigate the therapeutic potential of PA8 in NSCLC.

Related: Apoptosis Non-Small Cell Lung Cancer MET gene

Udager AM, Alva A, Chen YB, et al.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC): a rapid autopsy report of metastatic renal cell carcinoma.
Am J Surg Pathol. 2014; 38(4):567-77 [PubMed] Free Access to Full Article Related Publications
Rapid ("warm") autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)-the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient's RCC demonstrated extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.

Related: Kidney Cancer Skin Cancer

Caria P, Frau DV, Dettori T, et al.
Optimizing detection of RET and PPARg rearrangements in thyroid neoplastic cells using a home-brew tetracolor probe.
Cancer Cytopathol. 2014; 122(5):377-85 [PubMed] Related Publications
BACKGROUND: Fluorescence in situ hybridization (FISH) to identify specific DNA target sequences in the nuclei of nondividing cells of numerous solid neoplasms has contributed to the introduction of molecular cytogenetics as a useful adjunct to cytology, leading recently to the "marriage" of the 2 disciplines. Numerous cancer molecular markers can now be investigated using different technical approaches, at both the gene and expression levels, in biopsies of various suspected cancers, including differentiated thyroid carcinoma. The limited amount of bioptic material is often insufficient to carry out multiple tests, and optimizing handling of the biopsy is desirable.
METHODS: We have developed a home-brew tetracolor break-apart probe able to simultaneously identify the 2 most common genetic alterations in differentiated thyroid carcinoma: RET/PTC variants in papillary thyroid carcinoma and PAX8/PPARg fusion and variants in follicular thyroid carcinoma.
RESULTS: The probe had 100% specificity, 99.5% sensitivity, and ≥ 3% cutoff. The probe was tested on RET/PTC and PAX8/PPARg RT-PCR positive controls, and feasibility was assessed in 368 thyroid nodule fine-needle aspirations (FNA). In the latter analysis, 24 FNAs had split RET signal, and 9 had split PPARg signal. FISH analysis of available surgically removed nodules confirmed the sensitivity of FISH in detecting abnormal clones and oligoclones.
CONCLUSIONS: The home-brew tetracolor probe showed high feasibility, optimizing the use of the biological material in relation to the available molecular tests and maximizing the FISH experimental and slide-scoring times. This probe may be considered an alternative to RT-PCR when recovery and quality of RNA amplification from FNA are insufficient.

Related: FISH PPARG gene RET Thyroid Cancer

Zhu H, Xi Q, Liu L, et al.
Quantitative assessment of common genetic variants on FOXE1 and differentiated thyroid cancer risk.
PLoS One. 2014; 9(1):e87332 [PubMed] Free Access to Full Article Related Publications
Forkhead box E1 encodes the transcription factor FOXE1 (or TTF-2), which together with Homeobox protein NKX2-1, PAX8 and HHEX, are pivotal proteins required for thyroid gland formation, differentiation and function. Recently, genome-wide association studies have identified FOXE1 as a thyroid cancer (TC) susceptibility gene in populations of European descent. After that, a number of studies reported that the rs965513, rs1867277, and rs71369530 polymorphism in FOXE1 has been implicated in TC risk. However, the causal variants remain unknown. To derive a more precise estimation of the relationship, a meta-analysis of 9,828 TC cases and 109,995 controls from 14 case-control studies was performed. Overall, significant results were observed for rs965513 (OR=1.71, 95% CI: 1.59-1.85, P<10(-5)), rs1867277 (OR=1.64, 95% CI: 1.51-1.78, P<10(-5)) and rs71369530 (OR=2.01, 95% CI: 1.66-2.44, P<10(-5)) polymorphism. In the subgroup analysis by ethnicity, we found that rs965513 polymorphism confer high risk for Caucasians with per-allele OR of 1.80 (95% CI: 1.69-1.92, P<10(-5)) compared to East Asians of 1.35 (95% CI: 1.09-1.67, P=0.006). There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. In the subgroup analysis by sample size, and study design, significantly increased risks were found for the polymorphism. In conclusion, this meta-analysis demonstrated that common variations of FOXE1 are a risk factor associated with increased TC susceptibility.

Related: Thyroid Cancer

Hes O, de Souza TG, Pivovarcikova K, et al.
Distinctive renal cell tumor simulating atrophic kidney with 2 types of microcalcifications. Report of 3 cases.
Ann Diagn Pathol. 2014; 18(2):82-8 [PubMed] Related Publications
We report 3 cases of primary renal cell tumor simulating atrophic kidney with distinct gross, morphologic, immunohistochemical, and molecular genetic features. The tumors were retrieved out of more than 17 000 renal tumors from the Plzen Tumor Registry. Tissues for light microscopy had been fixed, embedded, and stained with hematoxylin and eosin using routine procedures. The tumors were further analyzed using immunohistochemistry, array comparative genomic hybridization, and human androgen receptor. Analyses of VHL gene and loss of heterozygosity (LOH) 3p were also performed. The patients were 2 women and 1 man, with ages ranging from 29 to 35 years (mean, 31.3 years). Grossly, the neoplasms were encapsulated and round with largest diameter of 3.5 cm (mean, 3.2 cm). Follow-up available for all patients ranged from 2 to 14 years (mean, 8 years). No aggressive behavior was noted. Histologically, akin to atrophic (postpyelonephritic) kidney parenchyma, the tumors were composed of follicles of varying sizes that were filled by eosinophilic secretion. Rare areas contained collapsed follicles. Each follicle was endowed with a small capillary. The stroma was loose, inconspicuous, and focally fibrotic. Two types of calcifications were noted: typical psammoma bodies and amorphous dark-blue stained calcified deposits. Immunohistochemically, tumors were strongly positive for cytokeratins (OSCAR), CD10, and vimentin, with weak immunopositivity for CAM5.2 and AE1-AE3. WT1 and cathepsin K were weakly to moderately focally to diffusely positive. Tumors were negative for cytokeratin 20, carbonic anhydrase IX, parvalbumin, HMB45, TTF1, TFE3, chromogranin A, thyroglobulin, PAX8, and ALK. Only 1 case was suitable for molecular genetic analyses. No mutations were found in the VHL gene; no methylation of VHL promoter was noted. No numerical aberrations were found by array comparative genomic hybridization analysis. LOH for chromosome 3p was not detected. Analysis of clonality (human androgen receptor) revealed the monoclonal nature of the tumor. We describe an unknown tumor of the kidney that (1) resembles renal atrophic kidney or nodular goiter of thyroidal gland; (2) contains a leiomyomatous capsule and 2 types of calcifications; (3) lacks mitoses, atypias, necroses, and hemorrhages and nearly lack Ki-67 positivity; and (4) so far showed benign biological behavior.

Related: CGH Kidney Cancer VHL AR: androgen receptor

de Biase D, Visani M, Pession A, Tallini G
Molecular diagnosis of carcinomas of the thyroid gland.
Front Biosci (Elite Ed). 2014; 6:1-14 [PubMed] Related Publications
Our understanding of the molecular pathology of thyroid cancer has progressed significantly. It is now apparent that thyroid tumors show a very good correlation between genotype and phenotype, a correlation that is much stronger than that observed in tumors of many other organs. Activation of classic oncogenes (BRAF, RAS, RET) activate MAPK signalling. Other pathways like the PI3K/PTEN/AKT cascade are also active in many thyroid tumors. The analysis of molecular profiles is generating data that can be applied to improve patient management. The common occurrence of thyroid nodules in the general population and the widespread use of fine needle aspiration for the preoperative diagnosis of thyroid nodules creates an unprecedented opportunity to apply what we have learnt from the molecular alterations of thyroid cancer to the clinical arena.

Related: FISH PPARG gene BRAF gene RET Thyroid Cancer KRAS gene

Szczepanek-Parulska E, Szaflarski W, Piątek K, et al.
Alternative 3' acceptor site in the exon 2 of human PAX8 gene resulting in the expression of unknown mRNA variant found in thyroid hemiagenesis and some types of cancers.
Acta Biochim Pol. 2013; 60(4):573-8 [PubMed] Related Publications
PAX8 gene encodes one of the transcription factors engaged in the regulation of proper development of thyroid gland as well as Müllerian and renal/upper urinary tracts. So far, six alternatively spliced transcripts were reported, however, sequences of only four were deposited in the NCBI database. Here, we evaluate a fragment of a novel variant of PAX8 mRNA formed by an alternative 3' acceptor site located in the second exon. The molecular outcome encompasses extension of the 5' untranslated region of exon two by 97 nucleotides as is evident from mRNA. This new insert may impair binding of mRNA to the ribosome and in consequence significantly decrease expression of the PAX8 protein. Here, we show for the first time that the novel insert in exon two might be associated with congenital thyroid hemiagenesis and influence development of different types of cancer.

Related: Cancer Prevention and Risk Reduction

Leeman-Neill RJ, Kelly LM, Liu P, et al.
ETV6-NTRK3 is a common chromosomal rearrangement in radiation-associated thyroid cancer.
Cancer. 2014; 120(6):799-807 [PubMed] Article available free on PMC after 15/03/2015 Related Publications
BACKGROUND: In their previous analysis of papillary thyroid carcinomas (PTCs) from an Ukrainian-American cohort that was exposed to iodine-131 ((131) I) from the Chernobyl accident, the authors identified RET/PTC rearrangements and other driver mutations in 60% of tumors.
METHODS: In this study, the remaining mutation-negative tumors from that cohort were analyzed using RNA sequencing (RNA-Seq) and reverse transcriptase-polymerase chain reaction to identify novel chromosomal rearrangements and to characterize their relation with radiation dose.
RESULTS: The ETS variant gene 6 (ETV6)-neurotrophin receptor 3 (NTRK3) rearrangement (ETV6-NTRK3) was identified by RNA-Seq in a tumor from a patient who received a high (131) I dose. Overall, the rearrangement was detected in 9 of 62 (14.5%) post-Chernobyl PTCs and in 3 of 151 (2%) sporadic PTCs (P = .019). The most common fusion type was between exon 4 of ETV6 and exon 14 of NTRK3. The prevalence of ETV6-NTRK3 rearrangement in post-Chernobyl PTCs was associated with increasing (131) I dose, albeit at borderline significance (P = .126). The group of rearrangement-positive PTCs (ETV6-NTRK3, RET/PTC, PAX8-PPARγ) was associated with significantly higher dose response compared with the group of PTCs with point mutations (BRAF, RAS; P < .001). In vitro exposure of human thyroid cells to 1 gray of (131) I and γ-radiation resulted in the formation of ETV6-NTRK3 rearrangement at a rate of 7.9 × 10(-6) cells and 3.0 × 10(-6) cells, respectively.
CONCLUSIONS: The authors report the occurrence of ETV6-NTRK3 rearrangements in thyroid cancer and demonstrate that this rearrangement is significantly more common in tumors associated with exposure to (131) I and has a borderline significant dose response. Moreover, ETV6-NTRK3 rearrangement can be directly induced in thyroid cells by ionizing radiation in vitro and, thus, may represent a novel mechanism of radiation-induced carcinogenesis.

Related: NTRK3 gene Thyroid Cancer USA ETV6 (TEL) gene

Chan JK
Newly available antibodies with practical applications in surgical pathology.
Int J Surg Pathol. 2013; 21(6):553-72 [PubMed] Related Publications
Selected antibodies that have become available in recent years and have applications in diagnostic pathology are discussed. They include antibodies that are organ-related, provide information on cellular differentiation or histogenetic type, have predictive value in tumors, and highlight infective agents. PAX8 (paired box gene 8) is a marker expressed in the lower female genital tract, thyroid, and kidney and their tumors. Napsin A is expressed in the lung and kidney and is an alternative marker for pulmonary adenocarcinoma. Arginase A is a sensitive and specific marker for liver tumors. ERG (Ets-related gene) is an excellent marker for endothelium and vascular tumors as well as prostatic cancer (about 50% of cases). SOX10 (SRY-related HMG box) is expressed predominantly in melanocytic and Schwann cells and the corresponding tumors. DOG1 (discovered on GIST 1) is an excellent marker for gastrointestinal stromal tumor (GIST) and acinic cell carcinoma. OCT3/4 is a pan-germ cell tumor marker, except yolk sac tumor. SALL4 is positive in various types of germ cell tumors, including yolk sac tumor. MUC4 (mucin-related antigen 4) is a sensitive and specific marker for low-grade fibromyxoid sarcoma. Langerin is a specific marker for Langerhans cells and their tumors. SOX11 is a sensitive marker for mantle cell lymphoma. New generation antibodies against anaplastic lymphoma kinase (ALK) are required to reliably demonstrate ALK gene translocation in pulmonary carcinomas. Lack of expression of succinate dehydrogenase B is seen in paragangliomas of the hereditary form and in the pediatric type of GIST. Antibodies against Trepenoma pallidum can facilitate the diagnosis of syphilis, whereas those against SV40 (simian virus 40) are helpful for diagnosis of BK virus infection and progressive multifocal leukoencephalopathy.

Related: Cancer Prevention and Risk Reduction

De Mattos-Arruda L, Bidard FC, Won HH, et al.
Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: the role of massively parallel sequencing.
Mol Oncol. 2014; 8(1):150-8 [PubMed] Related Publications
In this proof-of-principle study, we sought to define whether targeted capture massively parallel sequencing can be employed to determine the origin of metastatic deposits in cases of synchronous primary malignancies and metastases in distinct anatomical sites. DNA samples extracted from synchronous tumor masses in the breast, adnexal, and pelvic-peritoneal regions from a 62-year-old BRCA1 germline mutation carrier were subjected to targeted massively parallel sequencing using a platform comprising 300 cancer genes known to harbor actionable mutations. In addition to BRCA1 germline mutations, all lesions harbored somatic loss of the BRCA1 wild-type allele and TP53 somatic mutations. The primary breast cancer displayed a TP53 frameshift (p.Q317fs) mutation, whereas and the adnexal lesion harbored a TP53 nonsense (p.R213*) mutation, consistent with a diagnosis of two independent primary tumors (i.e. breast and ovarian cancer). The adnexal tumor and all pelvic-peritoneal implants harbored identical TP53 (p.R213*) and NCOA2 (p.G952R) somatic mutations. Evidence of genetic heterogeneity within and between lesions was observed, both in terms of somatic mutations and copy number aberrations. The repertoires of somatic genetic aberrations found in the breast, ovarian, and pelvic-peritoneal lesions provided direct evidence in support of the distinct origin of the breast and ovarian cancers, and established that the pelvic-peritoneal implants were clonally related to the ovarian lesion. These observations were consistent with those obtained with immunohistochemical analyses employing markers to differentiate between carcinomas of the breast and ovary, including WT1 and PAX8. Our results on this case of a patient with BRCA1-mutant breast and ovarian cancer demonstrate that massively parallel sequencing may constitute a useful tool to define the relationship, clonality and intra-tumor genetic heterogeneity between primary tumor masses and their metastatic deposits in patients with multiple primary malignancies and synchronous metastases.

Related: Breast Cancer Ovarian Cancer

Lau A, Kollara A, St John E, et al.
Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: implications for ovarian carcinogenesis.
Exp Biol Med (Maywood). 2014; 239(1):24-32 [PubMed] Related Publications
Evidence indicates that high-grade serous ovarian carcinoma (HGSOC) may originate from lesions within the distal fallopian tube epithelium (FTE). Our previous studies indicate that fallopian tube epithelial cells from carriers of germline mutations in breast cancer susceptibility genes exhibit a pro-inflammatory gene expression signature during the luteal phase, suggesting that delayed resolution of postovulatory inflammatory signaling may contribute to predisposition to this ovarian cancer histotype. To determine whether exposure of tubal epithelial cells to periovulatory follicular fluid alters expression of inflammation-associated genes, we used an ex vivo culture system of bovine oviductal epithelial cells. Oviductal cells grown on collagen IV-coated transwell membranes assumed a cobblestone appearance and immunocytochemistry for FoxJ1 and Pax8 indicated that both ciliated and secretory epithelial cells were maintained in the cultures. Oviductal cells were exposed to human follicular fluid or culture medium for 24 h following which total cellular RNA was extracted at various time points. Expression of genes associated with inflammation was determined by quantitative real-time RT-PCR. Exposure to follicular fluid transiently increased the transcript levels of interleukin 8 (IL8) and cyclooxygenase 2 (PTGS2), and decreased the expression of mitochondrial superoxide dismutase (SOD2), glutathione peroxidase 3 (GPX3), disabled homolog 2 (DAB2), and glucocorticoid receptor (NR3C1). Tumor necrosis factor (TNF) and IL6 levels were also decreased while those of nicotinomide phosphoribosyltransferase (NAMPT) were unaffected. This study demonstrates that periovulatory follicular fluid can act directly upon oviductal epithelial cells to alter gene expression that might contribute to early carcinogenic events. Furthermore, these findings illustrate the potential use of bovine oviductal cells to study signaling events implicated in ovarian carcinogenesis.

Related: Ovarian Cancer

Tanwar PS, Mohapatra G, Chiang S, et al.
Loss of LKB1 and PTEN tumor suppressor genes in the ovarian surface epithelium induces papillary serous ovarian cancer.
Carcinogenesis. 2014; 35(3):546-53 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Epithelial ovarian cancer presents mostly with serous, endometrioid or mucinous histology but is treated as a single disease. The development of histotype-specific therapy has been challenging because of the relative lack of studies attributing disrupted pathways to a distinct histotype differentiation. mTOR activation is frequently associated with poor prognosis in serous ovarian cancer, which is the most common and most deadly histotype. However, the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown. We detected copy number loss and correlated lower expression levels of LKB1, TSC1, TSC2 and PTEN tumor suppressor genes for upstream regulators of mTOR activity in up to 80% in primary ovarian serous tumor databases, with LKB1 allelic loss-predominant. Reduced LKB1 protein was usually associated with increased mTOR activity in both serous ovarian cancer cell lines and primary tumors. Conditional deletion of Lkb1 in murine ovarian surface epithelial (OSE) cells caused papillary hyperplasia and shedding but not tumors. Simultaneous deletion of Lkb1 and Pten, however, led to development of high-grade ovarian serous histotype tumors with 100% penetrance that expressed WT1, ERα, PAX8, TP53 and cytokeratin 8, typical markers used in the differential diagnosis of serous ovarian cancer. Neither hysterectomy nor salpingectomy interfered with progression of ovarian tumorigenesis, suggesting that neither uterine nor Fallopian tube epithelial cells were contributing to tumorigenesis. These results implicate LKB1 loss in the OSE in the pathogenesis of serous ovarian cancer and provide a compelling rationale for investigating the therapeutic potential of targeting LKB1 signaling in patients with this deadly disease.

Related: Ovarian Cancer PTEN

Gardi NL, Deshpande TU, Kamble SC, et al.
Discrete molecular classes of ovarian cancer suggestive of unique mechanisms of transformation and metastases.
Clin Cancer Res. 2014; 20(1):87-99 [PubMed] Related Publications
PURPOSE: Tumor heterogeneity and subsistence of high-grade serous ovarian adenocarcinoma (HGSC) classes can be speculated from clinical incidences suggesting passive tumor dissemination versus active invasion and metastases.
EXPERIMENTAL DESIGN: We explored this theme toward tumor classification through two approaches of gene expression pattern clustering: (i) derivation of a core set of metastases-associated genes and (ii) resolution of independent weighted correlation networks. Further identification of appropriate cell and xenograft models was carried out for resolution of class-specific biologic functions.
RESULTS: Both clustering approaches achieved resolution of three distinct tumor classes, two of which validated in other datasets. Networks of enriched gene modules defined biologic functions of quiescence, cell division-differentiation-lineage commitment, immune evasion, and cross-talk with niche factors. Although deviant from normal homeostatic mechanisms, these class-specific profiles are not totally random. Preliminary validation of these suggests that Class 1 tumors survive, metastasize in an epithelial-mesenchymal transition (EMT)-independent manner, and are associated with a p53 signature, aberrant differentiation, DNA damage, and genetic instability. These features supported by association of cell-specific markers, including PAX8, PEG3, and TCF21, led to the speculation of their origin being the fimbrial fallopian tube epithelium. On the other hand, Class 2 tumors activate extracellular matrix-EMT-driven invasion programs (Slug, SPARC, FN1, THBS2 expression), IFN signaling, and immune evasion, which are prospectively suggestive of ovarian surface epithelium associated wound healing mechanisms. Further validation of these etiologies could define a new therapeutic framework for disease management.

Related: Ovarian Cancer

Landa I, Boullosa C, Inglada-Pérez L, et al.
An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility.
PLoS One. 2013; 8(9):e74765 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Papillary Thyroid Cancer (PTC) is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010) and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017). Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.

Related: Thyroid Cancer

Koo J, Zhou X, Moschiano E, et al.
The immunohistochemical expression of islet 1 and PAX8 by rectal neuroendocrine tumors should be taken into account in the differential diagnosis of metastatic neuroendocrine tumors of unknown primary origin.
Endocr Pathol. 2013; 24(4):184-90 [PubMed] Related Publications
Rectal neuroendocrine tumors (NETs) can be classified by histologic pattern and secretory products. Recently, rectal NETs have been noted to exhibit immunohistochemical (IHC) positivity for Islet 1 and PAX8, which are generally considered markers for NETs of pancreatic origin. In this study, we sought to characterize the IHC staining profile of rectal NETs and determine whether there was any correlation between the histologic pattern of rectal NETs and their IHC profile. Fifty-six primary rectal NETs were histologically reviewed and stained with antibodies against Islet 1, PAX8, CDX2, chromogranin A, and synaptophysin. In a subset of 31 cases, immunoreactivity for serotonin, pancreatic polypeptide (PP), and prostatic acid phosphatase (PAP) was also studied. By morphology, the tumors studied included 55 % trabecular, 27 % solid nested, 4 % acinar, and 14 % mixed patterns. Islet 1 was positive in 89 % and PAX8 in 79 % of cases. CDX2 was negative in all 56 cases. Cytoplasmic staining was observed for chromogranin A in 30 % of cases and for synaptophysin in all 56 cases. Cytoplasmic staining for serotonin, PP, and PAP was present in 16, 61, and 97 % of cases, respectively. There was no correlation between histologic pattern and IHC staining pattern with any of the antibodies studied. We have demonstrated that Islet 1 and PAX8 are not entirely specific for NETs of pancreatic origin, as they are expressed in a majority of rectal NETs. Since rectal NETs may show an IHC staining profile which mirrors that of pancreatic NETs (Islet 1 and PAX8-positive, CDX2-negative), a metastatic rectal NET should be considered in the differential diagnosis and ruled out clinically in the work-up of a metastatic NET of unknown primary origin which exhibits this staining profile.

Related: Cancer of Unknown Primary CDX2 gene

Vu-Phan D, Grachtchouk V, Yu J, et al.
The thyroid cancer PAX8-PPARG fusion protein activates Wnt/TCF-responsive cells that have a transformed phenotype.
Endocr Relat Cancer. 2013; 20(5):725-39 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
A chromosomal translocation results in the production of a paired box 8-peroxisome proliferator-activated receptor gamma (PAX8-PPARG) fusion protein (PPFP) in ∼35% of follicular thyroid carcinomas. To examine the role of PPFP in thyroid oncogenesis, the fusion protein was stably expressed in the non-transformed rat thyroid cell line PCCL3. PPFP conferred on PCCL3 cells the ability to invade through Matrigel and to form colonies in anchorage-independent conditions. PPFP also increased the fraction of cells with Wnt/TCF-responsive green fluorescent protein reporter gene expression. This Wnt/TCF-activated population was enriched for colony-forming and invading cells. These actions of PPFP required a functional PPARG DNA binding domain (DBD) within PPFP and were further stimulated by PPARG agonists. These data indicate that PPFP, through its PPARG DBD, induces Wnt/TCF pathway activation in a subpopulation of cells, and these cells have properties of cellular transformation including increased invasiveness and anchorage-independent growth.

Related: PPARG gene Thyroid Cancer

Endo T, Kobayashi T
Concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to thyrocytes.
Endocr Relat Cancer. 2013; 20(6):767-76 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
A variant located on 14q13.3 nearest to thyroid transcription factor-1 (TTF1) predisposes individuals to thyroid cancer, but whether this variant is related to the RET/PTC rearrangement associated with human papillary thyroid carcinomas (PTCs) is unknown. The aims of this study were to investigate the effects of RET/PTC1 on the expression of thyroid-specific genes in thyrocytes and their relationship with malignant transformation of the thyrocytes. In the absence or presence of TSH, an extracellular signal-regulated kinase was phosphorylated in FRTL5 cells that stably expressed RET/PTC1, and these cells grew independently of TSH. FRTL (RET/PTC1) cells produced 566% more thyroglobulin mRNA and 474% more Na+/I- symporter mRNA than did the control FRTL (pcDNA) cells. FRTL (RET/PTC1) cells expressed 468% more Ttf1 mRNA than did FRTL (pcDNA) cells, but these two cell types did not differ significantly with respect to Pax8 or Ttf2 mRNA levels. When FRTL (RET/PTC1) cells and FRTL (pcDNA), cells were injected into each of nine nude mice, each mouse developed a single tumor at the site of FRTL (RET/PTC1) cell injection; in contrast, tumor formation never occurred at sites of FRTL (cDNA) cells injection. Tumors resulting from FRTL (RET/PTC1) cells retained (125)I-uptake activity; moreover, the cells invaded into surrounding skeletal muscle. When overexpression of Ttf1 in FRTL (RET/PTC1) cells was silenced, the cells completely lost their tumorigenic potential. Exogenous TTF1 cDNA enhanced the tumorigenicity of BHP18-21v cells, human PTC cells that express RET/PTC1, in nude mice. These results indicated that concurrent overexpression of RET/PTC1 and TTF1 confers tumorigenicity to FRTL5 and BHP18-21v cells in nude mice.

Related: Thyroid Cancer

Boaventura P, Pereira D, Celestino R, et al.
Genetic alterations in thyroid tumors from patients irradiated in childhood for tinea capitis treatment.
Eur J Endocrinol. 2013; 169(5):673-9 [PubMed] Related Publications
OBJECTIVE: Exposure to ionizing radiation at young age is the strongest risk factor for the occurrence of papillary thyroid carcinoma (PTC). RET/PTC rearrangements are the most frequent genetic alterations associated with radiation-induced PTC, whereas BRAF and RAS mutations and PAX8-PPARG rearrangement have been associated with sporadic PTC. We decided to search for such genetic alterations in PTCs of patients subjected in childhood to scalp irradiation.
DESIGN: We studied 67 thyroid tumors from 49 individuals irradiated in childhood for tinea capitis scalp epilation: 36 malignant (12 cases of conventional PTC (cPTC), two cPTC metastases, 20 cases of follicular variant PTC (FVPTC), one oncocytic variant of PTC and one follicular carcinoma) and 31 follicular thyroid adenomas.
METHODS: The lesions were screened for the BRAF(V600E) and NRAS mutations and for RET/PTC and PAX8-PPARG rearrangements.
RESULTS: BRAF(V600E) mutation was detected in seven of 14 (50%) cPTC and two of 20 FVPTC (10%) (P=0.019). NRAS mutation was present in one case of FVPTC (5%). RET/PTC1 rearrangement was found, by RT-PCR, in one of 17 cases (5.9%) and by fluorescence in situ hybridization in two of six cases (33%). PAX8-PPARG rearrangement was not detected in any carcinoma. None of the follicular adenomas presented any of the aforementioned genetic alterations.
CONCLUSIONS: The prevalence of BRAF(V600E) mutation in our series is the highest reported in series of PTCs arising in radiation-exposed individuals. The prevalence of RET/PTC1 rearrangement fits with the values recently described in a similar setting.

Related: PPARG gene BRAF gene Thyroid Cancer NRAS

Pan Z, Grizzle W, Hameed O
Significant variation of immunohistochemical marker expression in paired primary and metastatic clear cell renal cell carcinomas.
Am J Clin Pathol. 2013; 140(3):410-8 [PubMed] Related Publications
OBJECTIVES: To compare the immunohistochemical expression of diagnostic markers in primary clear cell renal cell carcinomas (RCCs) and their matched metastases.
METHODS: Tissue microarrays were constructed from 15 pairs of primary and metastatic clear cell RCCs and then evaluated for the immunohistochemical expression of renal cell carcinoma antigen (RCCA), kidney-specific cadherin, carbonic anhydrase IX (CAIX), and paired box genes 2 (PAX2) and 8 (PAX8).
RESULTS: There was significantly higher overall marker expression in metastatic tumors compared to their matched primaries (P < .001). Individually, there was greater CAIX, PAX2, and PAX8 expression and lower RCCA expression in metastatic tumors. Most importantly, a significant proportion of originally RCCA-positive tumors lost such expression in metastases.
CONCLUSIONS: Metastatic RCCs have significantly higher expression of PAX2 and PAX8 compared to primary RCCs. RCCA is not very reliable in this diagnostic setting, both because of its lower overall sensitivity and loss of expression in metastatic RCCs.

Related: Kidney Cancer

Vu-Phan D, Koenig RJ
Genetics and epigenetics of sporadic thyroid cancer.
Mol Cell Endocrinol. 2014; 386(1-2):55-66 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
Thyroid carcinoma is the most common endocrine malignancy, and although the disease generally has an excellent prognosis, therapeutic options are limited for patients not cured by surgery and radioiodine. Thyroid carcinomas commonly contain one of a small number of recurrent genetic mutations. The identification and study of these mutations has led to a deeper understanding of the pathophysiology of this disease and is providing new approaches to diagnosis and therapy. Papillary thyroid carcinomas usually contain an activating mutation in the RAS cascade, most commonly in BRAF and less commonly in RAS itself or through gene fusions that activate RET. A chromosomal translocation that results in production of a PAX8-PPARG fusion protein is found in follicular carcinomas. Anaplastic carcinomas may contain some of the above changes as well as additional mutations. Therapies that are targeted to these mutations are being used in patient care and clinical trials.

Related: Thyroid Cancer

Joehlin-Price AS, Huang JH, Brooks JS, et al.
PAX-8 expression in cutaneous ciliated cysts: evidence for Müllerian origin.
Am J Dermatopathol. 2014; 36(2):167-70 [PubMed] Related Publications
Cutaneous ciliated cysts (CCC) are exquisitely rare, benign cystic lesions demonstrating simple, ciliated epithelial linings reminiscent of fallopian tube epithelium. Most commonly, CCC show a predilection for the lower extremities of young reproductive age women and demonstrate immunohistochemical positivity for estrogen and progesterone receptors, supporting the theory that they are derived from ectopic Müllerian rests. PAX-8 is a paired box gene, important in the development of Müllerian and thyroid organs and has utility in the identification of tumors of Müllerian, renal, and thyroid origin. Prompted by the precedent studies on PAX-8 immunohistochemical expression in tumors of Müllerian origin, this article aimed to explore the utility of this antibody in defining the histogenesis of 2 bona fide cases of CCC, both occurring in young reproductive age women. Herein, 2 prototypic index cases of CCC with strong nuclear positivity for estrogen and progesterone receptors are shown to also have positive nuclear staining for PAX-8, further supporting their likely Müllerian origin. These data support the designation of these lesions as cutaneous Müllerian cysts, distinct from potential ciliated cysts of eccrine origin.

Proietti A, Sartori C, Borrelli N, et al.
Follicular-derived neoplasms: morphometric and genetic differences.
J Endocrinol Invest. 2013; 36(11):1055-61 [PubMed] Related Publications
BACKGROUND: The distinction between follicular adenomas (FAs) and well differentiated follicular and papillary carcinomas is often a demanding task and sometimes only intuitive.
AIM: We report an histomorphological evaluation of follicular neoplasms [FAs, follicular carcinomas (FCs), and follicular variant of papillary carcinomas (FVPTCs)], supported by a qualitative and quantitative image analysis and by a molecular characterization.
MATERIAL AND METHODS: Tumor fibrosis and haemorrhage, neoplastic capsule thickness, follicle diameter, number of neoplastic cells, nuclear diameter of neoplastic cells, vessels density, vessels area and intratumoral distribution were evaluated. Ras and BRAF mutations, RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements were analyzed. Correlations with clinico-pathological features have been studied.
RESULTS: We found that FAs had a more extensive intratumoral haemorrhage, while malignant neoplasms were characterized by an evident fibrosis, higher cellularity and larger size. FVPTCs had higher nuclear diameter; cells count was higher in the minimally invasive follicular thyroid carcinomas, as well as a thickener neoplastic capsule. The CD34 stain showed a higher microvessel density in the FVPTCs group. A higher peripheral vessels distribution was observed only in malignant neoplasms. We observed overall Ras mutations in 2.4% of adenomas, in 41.5% of FVPTCs, and in 44.8% of FCs. It is outstanding that there is a marked difference in the Ras mutation distribution between the benign and malignant tumors in our series.
CONCLUSIONS: We found that genotyping of Ras gene family together with an accurate analysis of selected morphological features could help in the differential diagnosis of follicular-derived thyroid neoplasms.

Related: BRAF gene Thyroid Cancer

Eszlinger M, Krogdahl A, Münz S, et al.
Impact of molecular screening for point mutations and rearrangements in routine air-dried fine-needle aspiration samples of thyroid nodules.
Thyroid. 2014; 24(2):305-13 [PubMed] Related Publications
BACKGROUND: The diagnostic limitations of thyroid fine-needle aspiration (FNA), such as the indeterminate category, can be partially overcome by molecular analyses. However, until now, rearrangements have only been detected in fresh FNA material and the number of follicular thyroid carcinomas (FTCs) was rather low in previous studies. We aimed at investigating the impact of point mutations and rearrangement detection in a set of routine air-dried FNA smears with a higher percentage of FTCs.
METHODS: RNA and DNA was extracted from 310 FNAs (164 indeterminate, 57 malignant, 89 benign) and corresponding formalin-fixed paraffin-embedded tissue (156 follicular adenomas [FAs], 32 FTCs, 44 papillary thyroid carcinomas [PTCs], 9 follicular variant PTCs, and 69 goiters). PAX8/PPARG and RET/PTC rearrangements were detected by qPCR, BRAF and RAS mutations by high-resolution melting PCR and by pyrosequencing.
RESULTS: Forty-seven mutations were detected in the FNAs: 22 BRAF, 13 NRAS, and 3 HRAS mutations, 8 PAX8/PPARG, and one RET/PTC-rearrangement. While the presence of a BRAF and RET/PTC mutation was associated with cancer in 100% of samples each, the presence of a RAS and PAX8/PPARG mutation was associated with cancer in only 12% and 50% of samples, respectively. In the indeterminate group 4 of 25 carcinomas were identified by molecular FNA screening, which increased the sensitivity from 67% (cytology alone) to 75% (cytology plus molecular screening).
CONCLUSION: Molecular screening for point mutations and rearrangements is feasible in air-dried FNAs. Although the impact of detecting point mutations and rearrangements in FNAs has most likely been overestimated in previous studies, molecular FNA analyses improve presurgical diagnostics. The detection of BRAF mutations in FNA may improve the choice of surgery and postsurgical treatment. Further data are necessary to elucidate the true impact of detecting RAS and PAX8/PPARG mutations in FNAs. The inclusion of additional rare somatic mutations and miRNA markers might further improve the impact of molecular FNA diagnostics.

Related: PPARG gene BRAF gene RET

Bellevicine C, Iaccarino A, Malapelle U, et al.
PAX8 is expressed in anaplastic thyroid carcinoma diagnosed by fine-needle aspiration: a study of three cases with histological correlates.
Eur J Endocrinol. 2013; 169(3):307-11 [PubMed] Related Publications
OBJECTIVE: It is difficult to diagnose anaplastic thyroid carcinoma (ATC) in a fine-needle aspiration (FNA) sample because, given the loss of morphological and immunophenotypical follicular thyroid features, its cytology resembles that of other undifferentiated neoplasms. Recent studies have shown that immunostaining for paired box gene 8 (PAX8), a transcription factor expressed in normal thyroid, is effective for diagnosing ATCs on histology. The aim of this study was to evaluate whether PAX8 could be used to identify ATCs on cytology also.
DESIGN AND METHODS: We selected three PAX8-immunostained undifferentiated FNA samples previously diagnosed as suspected ATCs, whose cell block had been negative for the expression of TGB and thyroid transcription factor-1. Matched histological samples, available in two cases, were also processed for PAX8 immunohistochemistry.
RESULTS: All three FNA samples were PAX8 positive. Two samples that had an epithelioid pattern showed a diffuse, intense nuclear signal. The third sample, which had a spindle-cell pattern, showed less intense and more patchy staining. Matched histology yielded overlapping results.
CONCLUSIONS: PAX8 immunocytochemistry can help cytopathologists to diagnose ATCs.

Related: Thyroid Cancer

Reddi HV, Driscoll CB, Madde P, et al.
Redifferentiation and induction of tumor suppressors miR-122 and miR-375 by the PAX8/PPARγ fusion protein inhibits anaplastic thyroid cancer: a novel therapeutic strategy.
Cancer Gene Ther. 2013; 20(5):267-75 [PubMed] Related Publications
Anaplastic thyroid cancer (ATC) is an aggressive, fatal disease unresponsive to traditional therapies, generating a need to develop effective therapies. The PAX8/PPARγ fusion protein (PPFP) has been shown to favorably modulate tumor growth in follicular thyroid cancer, prompting our evaluation of its efficacy to inhibit ATC cell and tumor growth in vitro and in vivo. PPFP was constitutively expressed in five ATC cell lines: BHT-101, FRO, C-643, KTC-2 and KTC-3, and inhibited cell growth in four of five cell lines and xenograft tumor growth in four of four cell lines. PPFP-mediated growth inhibition involved multiple mechanisms, including upregulation of miR-122 and miR-375, associated with decreased angiogenesis and AKT pathway inactivation, respectively. Also, PPFP expression resulted in marked increase of thyroid-specific marker transcripts, including PAX8, thyroid peroxidase (TPO), sodium iodide symporter (NIS) and thyroglobulin, to varying degrees by activating their respective promoters, suggesting that PPFP induced cellular redifferentiation. Functional studies demonstrate that increased NIS messenger RNA is not associated with increased 125I uptake. However, ectopic expression of wild-type NIS-induced perchlorate-sensitive iodine uptake, suggesting that endogenous NIS in ATC cell lines is defective. As current treatment for ATC is only palliative, overexpression of PPFP may offer a novel therapeutic strategy for the treatment of ATC.

Related: Thyroid Cancer

Yu XM, Jaskula-Sztul R, Ahmed K, et al.
Resveratrol induces differentiation markers expression in anaplastic thyroid carcinoma via activation of Notch1 signaling and suppresses cell growth.
Mol Cancer Ther. 2013; 12(7):1276-87 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
Anaplastic thyroid carcinoma (ATC) is an extremely aggressive malignancy with undifferentiated features, for which conventional treatments, including radioactive iodine ablation, are usually not effective. Recent evidence suggests that the Notch1 pathway is important in the regulation of thyroid cancer cell growth and expression of thyrocyte differentiation markers. However, drug development targeting Notch1 signaling in ATC remains largely underexplored. Previously, we have identified resveratrol out of over 7,000 compounds as the most potent Notch pathway activator using a high-throughput screening method. In this study, we showed that resveratrol treatment (10-50 μmol/L) suppressed ATC cell growth in a dose-dependent manner for both HTh7 and 8505C cell lines via S-phase cell-cycle arrest and apoptosis. Resveratrol induced functional Notch1 protein expression and activated the pathway by transcriptional regulation. In addition, the expression of thyroid-specific genes including TTF1, TTF2, Pax8, and sodium iodide symporter (NIS) was upregulated in both ATC cell lines with resveratrol treatment. Notch1 siRNA interference totally abrogated the induction of TTF1 and Pax8 but not of TTF2. Moreover, Notch1 silencing by siRNA decreased resveratrol-induced NIS expression. In summary, our data indicate that resveratrol inhibits cell growth and enhances redifferentiation in ATC cells dependent upon the activation of Notch1 signaling. These findings provide the first documentation for the role of resveratrol in ATC redifferentiation, suggesting that activation of Notch1 signaling could be a potential therapeutic strategy for patients with ATC and thus warrants further clinical investigation.

Related: Apoptosis Signal Transduction Thyroid Cancer NOTCH1 gene

Ganly I, Ricarte Filho J, Eng S, et al.
Genomic dissection of Hurthle cell carcinoma reveals a unique class of thyroid malignancy.
J Clin Endocrinol Metab. 2013; 98(5):E962-72 [PubMed] Related Publications
CONTEXT: Hurthle cell cancer (HCC) is an understudied cancer with poor prognosis.
OBJECTIVE: Our objective was to elucidate the genomic foundations of HCC.
DESIGN AND SETTING: We conducted a large-scale integrated analysis of mutations, gene expression profiles, and copy number alterations in HCC at a single tertiary-care cancer institution.
METHODS: Mass spectrometry-based genotyping was used to interrogate hot spot point mutations in the most common thyroid oncogenes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, and AKT1. In addition, common oncogenic fusions of RET and NTRK1 as well as PAX8/PPARγ and AKAP9-BRAF were also assessed by RT-PCR. Global copy number changes and gene expression profiles were determined in the same tumor set as the mutational analyses.
RESULTS: We report that the mutational, transcriptional, and copy number profiles of HCC were distinct from those of papillary thyroid cancer and follicular thyroid cancer, indicating HCC to be a unique type of thyroid malignancy. Unsupervised hierarchical clustering of gene expression showed the 3 groups of Hurthle tumors (Hurthle cell adenoma [HA], minimally invasive Hurthle cell carcinoma [HMIN], and widely invasive Hurthle cell carcinoma [HWIDE] clustered separately with a marked difference between HWIDE and HA. Global copy number analysis also indicated distinct subgroups of tumors that may arise as HWIDE and HMIN. Molecular pathways that differentiate HA from HWIDE included the PIK3CA-Akt-mTOR and Wnt/β-catenin pathways, potentially providing a rationale for new targets for this type of malignancy.
CONCLUSIONS: Our data provide evidence that HCC may be a unique thyroid cancer distinct from papillary and follicular thyroid cancer.

Related: Thyroid Cancer

Leeman-Neill RJ, Brenner AV, Little MP, et al.
RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with iodine-131 radiation dose and other characteristics.
Cancer. 2013; 119(10):1792-9 [PubMed] Article available free on PMC after 05/04/2015 Related Publications
BACKGROUND: Childhood exposure to iodine-131 from the 1986 nuclear accident in Chernobyl, Ukraine, led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited.
METHODS: Mutational analysis was performed on 62 PTCs diagnosed in a Ukrainian cohort of patients who were < 18 years old in 1986 and received 0.008 to 8.6 Gy of (131) I to the thyroid. Associations between mutation types and (131) I dose and other characteristics were explored.
RESULTS: RET/PTC (ret proto-oncogene/papillary thyroid carcinoma) rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARγ (paired box 8/peroxisome proliferator-activated receptor gamma) rearrangement were identified. A significant negative association with (131) I dose for BRAF and RAS point mutations and a significant concave association with (131) I dose, with an inflection point at 1.6 Gy and odds ratio of 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARγ rearrangements were found. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared with point mutations, rearrangements were associated with residence in the relatively iodine-deficient Zhytomyr region, younger age at exposure or surgery, and male sex.
CONCLUSIONS: These results provide the first demonstration of PAX8/PPARγ rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with (131) I dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and (131) I exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients.

Related: PPARG gene BRAF gene RET Thyroid Cancer

Witt RL, Ferris RL, Pribitkin EA, et al.
Diagnosis and management of differentiated thyroid cancer using molecular biology.
Laryngoscope. 2013; 123(4):1059-64 [PubMed] Related Publications
OBJECTIVES/HYPOTHESIS: To define molecular biology in clinical practice for diagnosis, surgical management, and prognostication of differentiated thyroid cancer.
DATA SOURCES: Ovid Medline 2006-2012
REVIEW METHODS: Manuscripts with clinical correlates.
RESULTS: Papillary thyroid carcinomas harbor point mutations of the BRAF and RAS genes or RET/PTC rearrangements, all of which activate the mitogen-activated protein kinase pathway. These mutually exclusive mutations are found in 70% of PTC. BRAF mutation is found in 45% of papillary thyroid cancer and is highly specific. Follicular carcinomas are known to harbor RAS mutation or PAX8/PPARγ rearrangement. These mutations are also mutually exclusive and identified in 70% of follicular carcinomas. Molecular classifiers measure the expression of a large number of genes on a microarray chip providing a substantial negative predictive value pending further validation.
CONCLUSIONS: 1) 20% to 30% of cytologically classified Follicular Neoplasms and Follicular Lesion of Undetermined Significance collectively are malignant on final pathology. Approximately 70% to 80% of thyroid lobectomies performed solely for diagnostic purposes are benign. Molecular alteration testing may reduce the number of unnecessary thyroid procedures, 2) may reduce the number of completion thyroidectomies, and 3) may lead to more individualized operative and postoperative management. Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ for follicular lesion of undetermined significance and follicular neoplasm improve specificity, whereas molecular classifiers may add negative predictive value to fine needle aspiration diagnosis.

Related: Thyroid Cancer


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