ret/PTC-1 Activation in Hashimoto Thyroiditis

Sheils, Orla; O’Leary, John; Uhlmann, V; Luttich, K; Sweeney, E. C.

doi:10.1177/106689690000800305

Cited by 119 publications

(70 citation statements)

References 12 publications

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“…Furthermore, immune recognition of RET/PTC transformed thyroid tissue may place negative selection pressure on di erentiated tumors. Consistent with this we (Wirtschafter et al, 1997) and others (Sheils et al, 2000) ®nd expression of RET/PTC in a majority of patients with Hashimoto's autoimmune thyroiditis. These data indicate the presence of premalignant thyroid cells, whereas the frequency of RET/PTC expression is reduced in overt cancer (Sugg et al, 1998).…”

Section: Discussionsupporting

confidence: 75%

Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice

Powell

Russell

et al. 2001

Oncogene

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Cancers develop and progress via activation of oncogenes and loss of tumor suppressor genes, a progression that can be recapitulated through cross breeding mouse strains harboring genetic mutations. To de®ne the role of RET/PTC3, p53 and Fhit in thyroid carcinogenesis, we intercrossed RET/PTC3 transgenics with p537/7 mice. This new strain, RET/PTC3 p537/7 , succumb to rapidly growing and strikingly large multilobed thyroid tumors containing mixtures of both well and poorly di erentiated, highly proliferative follicular epithelial cells. Interestingly, transplanted tumors from RET/ PTC3 p537/7 mice grew in SCID but not syngeneic immunocompetent mice indicating that these advanced tumors were immunogenic. RET/PTC3 protein expression was reduced to undetectable levels in tumors of older mice suggesting that the continued elevated expression of RET/PTC3 may not be necessary for tumor progression. Similarly, expression of Fhit protein was reduced in early tumors and undetected in older tumors irrespective of tumor histopathology. In contrast to RET/PTC3 p537/7 mice, RET/PTC3 Fhit7/7 mice did not develop advanced thyroid carcinomas. These studies support a model of human thyroid cancer whereby thyroid epithelium expresses RET/PTC3 protein at early stages of tumor development, followed by the reduction of RET/PTC3 and loss of p53 function with progressive reduction of Fhit protein expression coincident with malignant progression. Oncogene (2001) 20, 3235 ± 3246.

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Section: Discussionsupporting

confidence: 75%

Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice

Powell

Russell

et al. 2001

Oncogene

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“…Previous data have shown frequent expression of RP3 fusion gene at very early stages of cancer (38) and in thyroid tissue of patients with thyroid autoimmune disease, suggesting that this expression may underlie the coexistence of neoplasia (10,11) and autoimmunity. Studying the early stages of RP3 expression in mouse thyroid tissue will help to evaluate the inflammatory conditions within the organ observed at very early stages following thyroid transformation, but before carcinoma and/or autoimmune disease occurs.…”

Section: Discussionmentioning

confidence: 99%

“…One member of this fusion gene family, RET/PTC3 (RP3), is formed following a paracentric inversion involving c-RET and RFG/ ARA70 (8,9). Of note, RP3 can be found in thyroid tissue from patients with the chronic thyroid inflammatory disease, Hashimoto's thyroiditis (10,11). Likewise, somatic rearrangement of c-RET has been observed in irradiated human thyroid tissue grafts in SCID mice, supporting the notion that ionizing radiation is an etiologic agent for thyroid cancer (12).…”

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confidence: 99%

A Thyroid Tumor-Specific Antigen Formed by the Fusion of Two Self Proteins

Powell

Eisenlohr

Rothstein

2003

The Journal of Immunology

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Thyroid epithelial cells frequently express one or more members of the rearranged during transfection/papillary thyroid carcinoma (RET/PTC) fusion oncogene family during early stages of cancer, and fusion gene transcripts have been found in inflammatory conditions of the thyroid such as the autoimmune disease, Hashimoto’s thyroiditis. Because these oncogenes encode chimeric proteins, novel RET/PTC epitopes may be targets of antitumor immune responses. We have been interested in the RET/PTC3 (RP3) fusion protein because this family member is more frequently expressed in radiation-induced and childhood papillary carcinomas than other members of the fusion oncogene family. We hypothesized that the activated kinase of c-RET, in the form of RP3, when expressed in patients with thyroid disease, presents an unusual altered self target for T cell recognition. Interestingly, we find that immunization with mouse RP3 protein can induce a strongly immunogenic response to RP3, although this response is not directed against the peptide comprising the unique fusion region. Rather, the responses are specific for the carboxyl-terminal portion of RP3 that is derived from the self protein c-RET. Furthermore, transplantation of RP3-expressing thyroid tumors into naive mice resulted in leukocytic infiltration, tumor rejection, and induction of RP3-specific T cells. Thus, the somatic fusion of two unrelated self proteins results in the development of a uniquely immunogenic response directed against self epitopes within RP3. These studies may better define the mechanisms controlling the initiation of thyroid-specific immune responses and provide insight into the design of novel molecules for invoking tumor-specific immunity.

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“…ret/PTC (rearranged in transformation/papillary thyroid carcinoma) is a constitutively active tyrosine kinase frequently found in papillary thyroid carcinoma and autoimmune Hashimoto's thyroiditis. 37,38 This observation suggests that overexpression of MHC class II genes may represent a novel feature of malignant thyroid follicular epithelium, and may play a role in the evasion of the immune system.…”

Section: Hla Markersmentioning

confidence: 99%

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

et al. 2007

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Follicular variant of papillary thyroid carcinoma is a lesion that frequently causes difficulties from a diagnostic perspective in the laboratory. The purpose of this study was to interrogate a cohort of archival thyroid lesions using gene expression analysis of a panel of markers proposed to have utility as adjunctive markers in the diagnosis of thyroid neoplasia and follicular variant of papillary thyroid carcinoma in particular. Laser Capture Microdissection was used to procure pure cell populations for extraction. In addition a novel, multiplex preamplification technique was used to facilitate analysis of multiple targets. The panel comprised: HLA-DMA, HLA-DBQ1, CD74, CSNK1G2, IRF3, KRAS2, LYN, MT1K, MT1X, RAB23, TGFB1 and TOP2A, with CDKN1B as an endogenous control. Expression profiles for each target were generated using TaqMan s Real-Time PCR. HLA-DMA, HLA-DQB1, MT1X, CSNK1G2 and RAB23 were found to be differentially expressed (Po0.05) when comparing follicular adenoma and follicular variant of papillary thyroid carcinoma. Comparison of follicular adenoma and follicular thyroid carcinoma groups showed significant differential expression for MT1K, MT1X and RAB23 (Po0.05). Comparison of the papillary thyroid carcinoma group (classic and follicular variants) and the follicular adenoma group showed differential expression for CSNK1G2, HLA-DQB1, MT1X and RAB23 (Po0.05). Finally, KRAS2 was found to be differentially expressed (Po0.05) when comparing the papillary thyroid carcinoma and follicular thyroid carcinoma groups. This panel of molecular targets discriminates between follicular adenoma, papillary thyroid carcinoma, follicular variant of papillary thyroid carcinoma and follicular thyroid carcinoma by their expression repertoires. It may have utility for broader use in the setting of fine-needle aspiration cytology and could improve the definitive diagnosis of certain categories of thyroid malignancy.

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ret/PTC-1 Activation in Hashimoto Thyroiditis

Cited by 119 publications

References 12 publications

Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice

Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53−/− mice

A Thyroid Tumor-Specific Antigen Formed by the Fusion of Two Self Proteins

A molecular expression signature distinguishing follicular lesions in thyroid carcinoma using preamplification RT-PCR in archival samples

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