Ret oncogene activation in human thyroid neoplasms is restricted to the papillary cancer subtype.

Abstract

We have recently reported the activation of a new oncogene in human papillary thyroid carcinomas. This oncogene, papillary thyroid carcinoma (PTC), is a novel rearranged version of the ret tyrosine-kinase protooncogene. Thyroid neoplasms include a broad spectrum of malignant tumors, ranging from well-differentiated tumors to undifferentiated anaplastic carcinomas. To determine the frequency of ret oncogene activation, we analyzed 286 cases of human thyroid tumors of diverse histologic types. We found the presence of an activated form of the ret oncogene in 33 (19%) of 177 papillary carcinomas. By contrast, none of the other 109 thyroid tumors, which included 37 follicular, 15 anaplastic, and 18 medullary carcinomas, and 34 benign lesions, showed ret activation. (J. Clin. Invest. 1992. 89:1517-1522

Immunohistochemical Diagnosis of Papillary Thyroid Carcinoma

“…The ret gene, located on Chromosome 10q, encodes a transmembrane tyrosine kinase receptor (13)(14)(15). Ret is normally expressed in neural crestderived cells; normal thyroid follicular epithelial cells do not express ret (19).…”

“…However, in the majority of PCs, a gene rearrangement occurs that places the intracellular domain of the ret gene under the transcriptional control of one of several genes that are expressed in thyroid follicular epithelium (16). This chimeric gene, the ret/PTC oncogene, is specific to papillary carcinomas and encodes a protein product that contains the cytoplasmic portion of ret (13)(14)(15). Therefore, immunohistochemical detection of the carboxy terminus of the ret protein in thyroid follicular epithelial lesions serves as a reliable marker for papillary carcinoma (16).…”

“…The ret/PTC family of chimeric oncogenes result from several rearrangements involving the ret gene of chromosome 10q (13)(14)(15); they are specific to papillary carcinomas and are present in up to 77% of these tumors (16). The protein product of the ret/PTC oncogenes all contain the intracellular tyrosine kinase domain of the normal ret protooncogene product and can therefore be immunohistochemically detected with an antibody to the carboxy terminus of ret (16,17).…”

Differential loss of heterozygosity at 7q31.2 in follicular and papillary thyroid tumors

“…Rearrangements of the ret protooncogene have been reported in a minority of PTC (Grieco et al, 1990;Santoro et al, 1992) in some studies, whereas another study demonstrated RET translocations in 59% of adult onset PTCs (Williams et al, 1996).…”

“…The molecular alterations underlying the development of either PTC or FTC are poorly understood. Mutations in the ras proto-oncogene may represent an early event in follicular thyroid tumorigenesis (Lemoine et al, 1989;Suarez et al, 1990), while ret proto-oncogene rearrangements may be important in PTC (Grieco et al, 1990;Santoro et al, 1992, Williams et al, 1996. Unlike many common tumor types, mutations of p53 are seen infrequently in di erentiated thyroid cancer , though they are commonly present in anaplastic and poorly differentiated tumors (Ito et al, 1992).…”