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ret/PTC-1, -2, and -3 oncogene rearrangements in human thyroid carcinomas: implications for metastatic potential?
Abstract:
The ret/PTC oncogene is unique to papillary thyroid cancer. Three forms of this oncogene, formed by translocation of three different genes to the tyrosine kinase domain of the ret protooncogene, result in constitutive kinase activation. Correlation with clinical outcome is controversial; ret/PTC-1 has been suggested to predict aggressive behavior. There is no morphological description of ret/PTC-positive tumors. We analyzed 60 thyroid carcinomas for ret/PTC expression to determine correlation with clinical history, disease stage, or tumor morphology. Ribonucleic acid extracted from frozen tissue was reverse transcribed; PCR was performed to amplify ret/PTC-1, 2, and -3. The TPC-1 cell line was the positive control for ret/PTC-1. All tumors were characterized morphologically. Clinical data were collected. The 57 papillary and 3 follicular carcinomas were resected from 44 female patients and 15 males. The average age at diagnosis was 46.2 yr (range. 24-83 yr). Three patients had a history of neck irradiation. At diagnosis, 11 patients had extrathyroidal tumor extension, 20 had lymph node metastases, and 1 had lung metastasis. Thirteen patients had tall cell papillary carcinomas; 3 tumors had focal insular or anaplastic dedifferentiation. The average follow-up was 13.4 months, during which 4 patients had recurrent disease. No deaths occurred. One papillary carcinoma (1.7%) was positive for ret/PTC-1, none was positive for ret/PTC-2, and 2(3.4%) were positive for ret/PTC-3. Although all 3 patients who had tumors containing ret/PTC rearrangements were under the age of 45 yr (range, 26-44 yr) and had small tumors (< 1.2 cm), 2 of these 3 patients presented with lymph node metastases, and the third had lymphatic invasion. ret/PTC oncogene expression did not correlate with radiation history. In summary, ret/PTC oncogene rearrangements were found in 3 of 60 (5%) thyroid carcinomas and were not present in tumors with aggressive morphological features. However, we found ret/PTC rearrangements in young patients (< 45 yr of age) with small thyroid carcinomas showing a predisposition for lymphatic involvement, suggesting a possible role in the development of this subgroup of tumors.
Insights
Retinoblastoma (ret)/papillary thyroid carcinoma (PTC) oncogene rearrangements were found in 5% of thyroid cancers. These rearrangements were not linked to aggressive features but were observed in younger patients with small tumors and a tendency for lymphatic spread.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The ret/PTC oncogene is specific to papillary thyroid cancer and results from gene translocations activating its tyrosine kinase domain.
- Previous studies suggested a correlation between ret/PTC-1 expression and aggressive thyroid cancer behavior, but this remains controversial.
- Morphological descriptions of ret/PTC-positive tumors are lacking.
Purpose of the Study:
- To analyze ret/PTC oncogene expression in thyroid carcinomas.
- To correlate ret/PTC expression with clinical history, disease stage, and tumor morphology.
- To investigate the potential role of ret/PTC rearrangements in specific thyroid cancer subgroups.
Main Methods:
- Sixty thyroid carcinomas were analyzed for ret/PTC-1, -2, and -3 expression using reverse transcription and polymerase chain reaction (PCR).
- Tumor morphology was characterized, and clinical data, including patient history, disease stage, and follow-up, were collected.
- The TPC-1 cell line served as a positive control for ret/PTC-1.
Main Results:
- Ret/PTC oncogene rearrangements were detected in 3 out of 60 (5%) thyroid carcinomas: one papillary carcinoma for ret/PTC-1 (1.7%) and two for ret/PTC-3 (3.4%). No ret/PTC-2 was found.
- These ret/PTC-positive tumors were found in patients under 45 years old, with small tumor size (<1.2 cm), but two presented with lymph node metastases and one with lymphatic invasion.
- Ret/PTC expression did not correlate with radiation history or aggressive morphological features such as tall cell, insular, or anaplastic dedifferentiation.
Conclusions:
- Ret/PTC oncogene rearrangements are infrequent in thyroid carcinomas and are not associated with aggressive morphological features.
- However, ret/PTC rearrangements were identified in a subgroup of young patients with small papillary thyroid carcinomas exhibiting a predisposition for lymphatic involvement.
- These findings suggest a potential role for ret/PTC rearrangements in the development of this specific subset of thyroid tumors.