Expression of the <i>RET/PTC</i> Fusion Gene as a Marker for Papillary Carcinoma in Hashimoto's Thyroiditis

Wirtschafter, Ari; Schmidt, Richard R.; Rosen, David; Kundu, Nandita; Santoro, Massimo; Fusco, Alfredo; Multhaupt, Hinke A.B.; Atkins, Joseph P.; Rosen, Marc; Keane, William M.; Rothstein, Jay L.

doi:10.1097/00005537-199701000-00019

Cited by 239 publications

(156 citation statements)

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“…All benign nodules were nonimmunoreactive for ret. Although ret has been occasionally reported in nonneoplastic follicular cells in chronic lymphocytic thyroiditis (16,20) and we have seen immunoreactivity in this setting (unpublished data), this is not usually a dilemma in the histological diagnosis of malignancy because this is a diffuse process rather than a discrete nodule.…”

Section: Figure 2 Immunohistochemistry For Ck19mentioning

confidence: 43%

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

et al. 2001

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In thyroid, the diagnosis of papillary carcinoma (PC) is based on nuclear features; however, identification of these features is inconsistent and controversial. Proposed markers of PC include HBME-1, specific cytokeratins (CK) such as CK19, and ret, the latter reflecting a ret/PTC rearrangement. We applied immunohistochemical stains to determine the diagnostic accuracy of these three markers. . HBME-1 and ret were negative in all NH and FA; some of these exhibited focal CK19 reactivity in areas of degeneration. Half of the FC and AC exhibited HBME-1 staining but no positivity for CK19 or ret. In PC, 20% of cases stained for all three markers. Classical PC had the highest positivity with staining for HBME-1 in 70%, CK19 in 80%, and ret in 78%. FVPC were positive for HBME-1 in 45%, for CK19 in 57%, and for ret in 63%; only 7 FVPC were negative for all three markers. The six IC exhibited 67% staining for HBME-1 and 50% positivity for CK19 and ret. The seven HCC had 29% positivity for HBME-1 and CK19, and 57% positivity for ret. This panel of three immunohistochemical markers provides a useful means of diagnosing PC. Focal CK19 staining may be found in benign lesions, but diffuse positivity is characteristic of PC. HBME-1 positivity indicates malignancy but not papillary differentiation. Only rarely are all three markers negative in PC; this panel therefore provides an objective and reproducible tool for the analysis of difficult thyroid nodules.

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Section: Figure 2 Immunohistochemistry For Ck19mentioning

confidence: 43%

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

et al. 2001

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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: 95%

“…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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“…This means that cytogenetic changes are likely due to the derangement of the cell cycle regulatory machinery rather than to the inflammatory parenchymal alterations. Although the detection of molecular alterations in HT, such as the presence of the papillary carcinoma-related fusion gene RET/PTC, is still a matter of discussion, the loss of genetic material at specific chromosomal loci has been demonstrated by Hunt and co-workers (Wirtschafter et al, 1997;Hunt et al, 2002;Nikiforova et al, 2002). We show here that LOH for a microsatellite located in the chromosomal region 7q32 -34, previously reported in PTC, also occurs in some galectin-3-positive focal undefined lesions detected in HTs.…”

Section: Discussionmentioning

confidence: 99%

Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis

Gasbarri

Sciacchitano²,

Marasco

et al. 2004

Br J Cancer

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Hashimoto's thyroiditis (HT) represents the most common cause of hypothyroidism and nonendemic goiter, but its clinical and pathological heterogeneity opens the question if this disease should be more properly considered as a spectrum of different thyroid conditions rather than as a single nosological entity. In this study, we analysed 133 cases of HT for the expression of galectin-3, a lectin molecule involved in malignant transformation, apoptosis and cell cycle control. An unexpected expression of galectin-3 was demonstrated in a subset of HT together with the presence of HBME-1, c-met and cyclin-D1 that are also involved in malignant transformation and deregulated cell growth. Furthermore, a loss of allelic heterozygosity in a specific cancer-related chromosomal region was demonstrated in some HT harbouring galectin-3-positive follicular cells, by using laser capture microdissection. On the basis of the morphological and molecular findings we identified four subsets of HT: (a) HT with classic features of chronic autoimmune thyroiditis; (b) HT associated to hyperplastic/adenomatous lesions; (c) HT harbouring thyroid cancer precursors; (d) HT associated to unequivocal thyroid microcarcinomas. Our findings provide a well-substantiated morphological and molecular demonstration that HT may include a spectrum of different thyroid conditions ranging from chronic autoimmune thyroiditis to thyroiditis triggered by specific immune-response to cancer-related antigens.

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Expression of the RET/PTC Fusion Gene as a Marker for Papillary Carcinoma in Hashimoto's Thyroiditis

Cited by 239 publications

References 6 publications

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

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

Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto's thyroiditis

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