Expression and alternative splicing of c-ret RNA in papillary thyroid carcinomas

Fluge, Øystein; Haugen, Dagny Faksvåg; Akslen, Lars A.; Marstad, Anne; Santoro, Massimo; Fusco, Alfredo; Varhaug, Jan Erik; Lillehaug, Johan R.

doi:10.1038/sj.onc.1204161

Cited by 37 publications

(33 citation statements)

References 24 publications

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“…The expression level is variable, particularly among tumor samples, explaining the apparent inconsistency of the reported detection rates. [8][9][10] The levels of c-RET expression are in any case B1000 times lower when compared to the control TT medullary carcinoma cell line. The expression level of RET exons 12-13 in individual cases is statistically higher relative to that of exons 10-11 only in those cases which express high levels of rearranged RET.…”

Section: Discussionmentioning

confidence: 99%

“…10 Similar to RET/PTC, c-RET mRNA has been reported in a variable proportion of papillary carcinomas with frequencies ranging from 21% 10 to 100%. 8,9 To address the issue of the expression level of RET and its rearranged forms in thyroid papillary carcinoma we have utilized real-time RT-PCR and quantitatively analyzed high-quality RNA extracted from frozen samples for the expression of RET/ PTC1, RET/PTC3 and RET exons 10-11 and 12-13, which are adjacent to the RET/PTC rearrangement site. RET/PTC1 was detectable in 18/25 (72%) papillary carcinomas.…”

Section: Discussionmentioning

confidence: 99%

“…[7][8][9][10][11] Wild-type RET may coexist with RET/ PTC 9,10 and it has been proposed as a marker for aggressive disease. 10 Similar to RET/PTC, c-RET mRNA has been reported in a variable proportion of papillary carcinomas with frequencies ranging from 21% 10 to 100%.…”

Section: Discussionmentioning

confidence: 99%

“…Although its signifi-cance is unclear, c-RET may also play a role in thyroid tumorigenesis. [7][8][9][10][11] Analysis of the data published in the literature suggests a wide range in the expression levels of RET/PTC and c-RET in tumor samples. This may contribute more than geographical factors to the differences in the reported frequencies of c-RET and, particularly, of RET/PTC detection.…”

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confidence: 99%

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Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

Rhoden

Johnson

Brandao

et al. 2004

Laboratory Investigation

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RET/PTC1 and RET/PTC3 are the markers for papillary thyroid carcinoma. Their reported prevalence varies broadly. Nonrearranged c-RET has also been detected in a variable proportion of papillary carcinomas. The published data suggest that a wide range in expression levels may contribute to the different frequency of c-RET and, particularly, of RET/PTC detection. However, quantitative expression analysis has never been systematically carried out. We have analyzed by real-time RT-PCR 25 papillary carcinoma and 12 normal thyroid samples for RET/PTC1, RET/PTC3 and for RET exons 10-11 and 12-13, which are adjacent to the rearrangement site. The variability in mRNA levels was marked and four carcinoma groups were identified: one lacking RET/ PTC rearrangement with balanced RET exon levels similar to those of the normal samples (7/25 cases, 28%), the second (6/25 cases, 24%) with balanced RET expression and very low levels of RET/PTC1, the third with unbalanced RET exons 10-11 and 12-13 expression, high RET/PTC1 levels but no RET/PTC3 (7/25 cases, 28%), and the fourth with unbalanced RET expression, high RET/PTC1 levels and low levels of RET/PTC3 (5/25 cases, 20%). Papillary carcinomas with high RET/PTC1 expression showed an association trend for large tumor size (P ¼ 0.063). Our results indicate that the variability in c-RET and RET/PTC mRNA levels contributes to the apparent inconsistencies in their reported detection rates and should be taken into account not only for diagnostic purposes but also to better understand the role of c-RET activation in thyroid tumorigenesis. Oncogenic c-RET activation in thyroid tumors composed of follicular cells is the result of chromosomal rearrangements resulting in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5 0 -terminal region of heterologous genes. The rearrangements are a molecular marker for papillary thyroid carcinoma as their very name, RET/PTC for papillary thyroid carcinoma, implies, 1 and consist of balanced inversions or translocations that involve the 3.0 kb intron 11 of c-RET. To date, at least 16 chimeric mRNAs affecting 11 different genes have been reported (Saenko et al, 2 reviewed in Tallini and Asa 3 ), of which RET/PTC1 (consisting of the fusion of RET with H4) and RET/PTC3 (consisting of the fusion of RET with RFG/ELE1) are by far the most common. 3 Their prevalence varies broadly from zero to more than 60% in nonradiation-associated cases 3 and is close to 90% in some series of papillary carcinomas from the Chernobyl area diagnosed after the 1986 nuclear disaster. 4 While the high prevalence of RET/PTC in radiation-associated thyroid tumors is consistent with misrepair of radiationinduced double-strand DNA breaks, 5,6 the high variability in the prevalence of RET/PTC in sporadic tumors has no specific explanation. In addition to rearranged RET forms, c-RET expression has also been identified in a highly variable proportion of papillary carcinoma samples. Although its signifi-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

Rhoden

Johnson

Brandao

et al. 2004

Laboratory Investigation

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“…16 Finally, full-length RET proteins are expressed not only in MTC 17 but also at low levels in PTC, regardless of the occurrence of RET rearrangements. 18,19 Despite this data, the oncogenic activity of RET point mutants for epithelial thyroid follicular cells has never been investigated.…”

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confidence: 99%

The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma

Melillo

Cirafici

Falco

et al. 2004

The American Journal of Pathology

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Activating germ-line point mutations in the RET receptor are responsible for multiple endocrine neoplasia type 2-associated medullary thyroid carcinoma (MTC), whereas somatic RET rearrangements are prevalent in papillary thyroid carcinomas (PTCs). Some rare kindreds, carrying point mutations in RET, are affected by both cancer types, suggesting that, under specific circumstances, point mutations in RET can drive the generation of PTC. Here we describe a family whose siblings, affected by both PTC and MTC, carried a germ-line point mutation in the RET extracellular domain, converting cysteine 634 into serine. We tested on thyroid follicular cells the transforming activity of RET(C634S), RET(K603Q), another mutant identified in a kindred with both PTC and MTC, RET(C634R) a commonly isolated allele in MEN2A, RET(M918T) responsible for MEN2B and also identified in kindreds with both PTC and MTC, and RET/ PTC1 the rearranged oncogene that characterizes bona fide PTC in patients without MTC. We show that the various RET point mutants, but not wild-type RET, scored constitutive kinase activity and exerted mito- Medullary thyroid carcinoma (MTC) is a malignant tumor arising from neural crest-derived calcitonin-secreting C cells of the thyroid, 1 whereas papillary thyroid carcinoma (PTC) derives from endoderm-derived follicular cells. 2 MTC often occurs in the context of autosomal dominant multiple endocrine neoplasia type 2 syndromes (MEN2), whereas PTC is sporadic in most of the cases. 3 This notwithstanding, some rare MEN2 kindreds are affected by both cancer types, the molecular mechanism for this association still remaining unclear.Both MTC and PTC are strictly linked to activating mutations in the RET gene. RET is a transmembrane tyrosine kinase receptor for glial-derived neurotrophic factor (GDNF). 4 RET rearrangements, caused by chromosomal inversions or translocations, are present in 20 to 40% of cases of PTC. 5 These rearrangements result in

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Identification of candidates for tumor‐specific alternative splicing in the thyroid

Guimarães

Latini

Camacho

et al. 2006

Genes Chromosomes & Cancer

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Alternative splicing is the differential processing of exon junctions to produce a new transcript variant from one gene. Some aberrant splicing, however, has been shown to be cancer specific. Identification of these specific splice variations will provide important insight into the molecular mechanism of normal cellular physiology as well as the disease processes. To gain knowledge about whether alternative splicing is linked to thyroid tumorigenesis, we used our prediction database to select targets for analysis. Fifteen putatively new alternative splicing isoforms were selected on the basis of their expression in thyroid libraries and/or their origin in genes previously associated with carcinogenesis. Using a set of 66 normal, benign, and malignant thyroid tissue samples, new splicing events were confirmed by RT-PCR for 13 of 15 genes (a validation rate of 87%). In addition, new alternative splicing isoforms not predicted by the system and not previously described in public databases were identified. Five genes (PTPN18, ABI3BP, PFDN5, SULF2, and ST5) presented new and/or additional unpredicted isoforms differentially expressed between malignant and benign or normal thyroid tissues, confirmed by sequencing. PTPN18, ABI3BP, and PFDN5 revealed a statistically significant differential splicing profile. In addition, real-time PCR analysis revealed that expression of an alternative PFDN5 variant was higher in malignant lesions than in benign lesions or normal tissues.

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Expression and alternative splicing of c-ret RNA in papillary thyroid carcinomas

Cited by 37 publications

References 24 publications

Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

Real-time quantitative RT-PCR identifies distinct c-RET, RET/PTC1 and RET/PTC3 expression patterns in papillary thyroid carcinoma

The Oncogenic Activity of RET Point Mutants for Follicular Thyroid Cells May Account for the Occurrence of Papillary Thyroid Carcinoma in Patients Affected by Familial Medullary Thyroid Carcinoma

Identification of candidates for tumor‐specific alternative splicing in the thyroid

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