Di CJ, Marcy M, Vasko V, Sebag F, Fakhry N, Wynford-Thomas D et al.. Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant. Hum Pathol 37: 824-830

Faculté de Médecine, Institut National de la Santé et de la Recherche Médicale (U555), 13385 Marseille Cedex 5, France.
Human Pathlogy (Impact Factor: 2.77). 08/2006; 37(7):824-30. DOI: 10.1016/j.humpath.2006.01.030
Source: PubMed


Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.

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Available from: Vasily V Vasko, Sep 24, 2014
    • "With this analysis we identified the regions that were differentially gained, lost or amplified between the 14 oncocytic and 11 non-oncocytic thyroid samples. A more complex genomic constellation is appreciated in the oncocytic group, strengthening the hypothesis that CNAs might Table 2. Summary of canonical BRAF and RAS hot-spot mutations frequency in oncocytic thyroid le- sions Reference Type of Analyzed oncocytic samples (n= case number) BRAF V600E mutation frequency (type of mutated thyroid tumor) H-, N-, K-RAS mutations frequency (type of mutated thyroid tumor) [51] FTC-O (n=11) NP 55% (FTC-O) [14] FA-O, FTC-O (n=11) NP 9.1% (FTC-O) [52] FTC-O (n=3) 0% NP [53] FTC-O, FA-O (n=22) 0% NP [13] FTC-O, FA-O (n=32) NP 9.4% (FTC-O, FA-O) [54] FA-O, FTC-O, PTC-O (n=39)^ 27.3% (PTC-O) NP [55] FTC-O (n=9) 0% 0% § [56] PTC-O -FV (n=3) 0% 0% [57] FA-O, FTC-O, PTC-O (n= 44) 0% 0% [58] FA-O, FTC-O (n=70) NP 11.4% (FTC-O) [59] PTC-O (n=9) 0% NP [11] FTC-O, PTC-O (n=13) 23% (PTC-O) 0% [60] PTC-O (n=8) 87.5% (PTC-O) NP [61] FTC-O, FA-O (n=20) 0% 5.8% (FTC-O) [12] FA-O, FTC-O, (n=27) 0% 11% (FTC-O) Present study Hyp-O, FA-O, PTC-O, FTC-O (n=14) 0% 0% ^Warthin-like PTCs were not considered; §Only N-RAS gene was analyzed. aCGH profiling of oncocytic thyroid lesions 1962 Am J Cancer Res 2015;5(6):1954-1971 contribute to development of oncocytic phenotype (Figure 5). "
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    ABSTRACT: Oncocytic change is the result of aberrant mitochondrial hyperplasia, which may occur in both neoplastic and non-neoplastic cells and is not infrequent in the thyroid. Despite being a well-characterized histologic phenotype, the molecular causes underlying such a distinctive cellular change are poorly understood. To identify potential genetic causes for the oncocytic phenotype in thyroid, we analyzed copy number alterations in a set of oncocytic (n=21) and non-oncocytic (n=20) thyroid lesions by high-resolution microarray-based comparative genomic hybridization (aCGH). Each group comprised lesions of diverse histologic types, including hyperplastic nodules, adenomas and carcinomas. Unsupervised hierarchical clustering of categorical aCGH data resulted in two distinct branches, one of which was significantly enriched for samples with the oncocytic phenotype, regardless of histologic type. Analysis of aCGH events showed that the oncocytic group harbored a significantly higher number of genes involved in copy number gains, when compared to that of conventional thyroid lesions. Functional annotation demonstrated an enrichment for copy number gains that affect genes encoding activators of mitochondrial biogenesis in oncocytic cases but not in their non-oncocytic counterparts. Taken together, our data suggest that genomic alterations may represent additional/alternative mechanisms underlying the development of the oncocytic phenotype in the thyroid.
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    • "First strand cDNA was synthesized from the RNA sample by SuperScript II RT kit (Invitrogen) with 5 mg of RNA per sample. Primers for full-length coding sequence of p53 (forward primer: 5 0 -AAGGATCCAAGAGGAGCCGCAGT-3 0 ; reverse primer: 5 0 -GCGAATTCTCAGTCTGAGTCAGG-3 0 ) and primers for amplifying H-ras, N-ras and K-ras genes (H-Ras: forward primer: 5 0 -ATGACGGAATATAAGCTGGT-3 0 ; reverse primer: 5 0 -AGGAAGCCCTCCCCGGTGCG-3 0 ; K-Ras: forward primer: 5 0 -ATGACGGAATATAAGCTGGT-3 0 ; reverse primer: 5 0 -CACAAAGAAAGCCCTCCCCA-3 0 ; N-Ras: forward primer: 5 0 -ATGACTGAGTACAAACTGGT-3 0 ; reverse primer: 5 0 -GTAGAGGTTAATATCCGCAA-3 0 ) were used as described (Di et al., 2006). The PCR conditions were as follows: for P53: 35 cycles of 941C for 1 min, 501C for 1 min, 721C for 2 min; for Ras: 35 cycles of 941C for 45 s, 501C for 45 s, 721C for 1 min. "
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    ABSTRACT: The mitotic arrest deficient 2 (MAD2) is suggested to play a key role in a functional mitotic checkpoint because of its inhibitory effect on anaphase-promoting complex/cyclosome (APC/C) during mitosis. The binding of MAD2 to mitotic checkpoint regulators MAD1 and Cdc20 is thought to be crucial for its function and loss of which leads to functional inactivation of the MAD2 protein. However, little is known about the biological significance of this MAD2 mutant in human cells. In this study, we stably transfected a C-terminal-deleted MAD2 gene (MAD2DeltaC) into a human prostate epithelial cell line, Hpr-1 and studied its effect on chromosomal instability, cell proliferation, mitotic checkpoint control and soft agar colony-forming ability. We found that MAD2DeltaC was able to induce aneuploidy through promoting chromosomal duplication, which was a result of an impaired mitotic checkpoint and cytokinesis, suggesting a crucial role of MAD2-mediated mitotic checkpoint in chromosome stability in human cells. In addition, the MAD2DeltaC-transfected cells displayed anchorage-independent growth in soft agar after challenged by 7,12-dimethylbenz[A]anthracene (DMBA), demonstrating a cancer-promoting effect of a defective mitotic checkpoint in human cells. Furthermore, the DMBA-induced transformation was accompanied by a complete loss of DNA damage-induced p53 response and activation of the MAPK pathway in MAD2DeltaC cells. These results indicate that a defective mitotic checkpoint alone is not a direct cause of tumorigenesis, but it may predispose human cells to carcinogen-induced malignant transformation. The evidence presented here provides a link between MAD2 inactivation and malignant transformation of epithelial cells.
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    ABSTRACT: Carcinomas of the thyroid comprise a heterogeneous group of neoplasms with distinctive clinical and pathological characteristics. Over the past 15 years, the application of molecular technologies to the study of these neoplasms has elucidated critical genetic pathways associated with the development of specific thyroid tumor types. In papillary thyroid carcinoma (PTC), genetic events involve RET and TRK (rearrangements) and BRAF and RAS (mutations), although RAS mutations are uncommon except in the follicular variant of PTC. These genetic alterations, which rarely overlap in the same tumor, result in signaling abnormalities in the mitogen-activated protein kinase pathway. In contrast, genetic alterations in follicular carcinomas include PAX8-PPARgamma translocations and RAS mutations while mutations of CTNNB1 and p53 have been implicated in the development and progression of poorly differentiated and undifferentiated (anaplastic) thyroid carcinomas. Germline mutations of RET are responsible for the development of heritable forms of medullary thyroid carcinoma (MTC) while somatic mutations of this oncogene are found in a significant proportion of sporadic MTCs. The results of these studies not only have provided additional approaches to thyroid tumor classification, but also have stimulated the development of novel approaches to tumor diagnosis and additional parameters for prognostic assessment and potential biologic therapeutic strategies.
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