The transcription coactivator HTIF1 and a related protein are fused to the RET receptor tyrosine kinase in childhood papillary thyroid carcinomas.
(17/1566)
Children exposed to radioactive iodine as a consequence of the Chernobyl reactor accident have an increased risk of papillary thyroid carcinomas (PTC). The predominant molecular lesions in these tumors are rearrangements of the RET receptor tyrosine kinase (tk). Here we report on two novel types of RET rearrangement, PTC6 and 7, and describe the fusion products and the ret fused gene (rfg) proteins. Like the other rfg proteins identified so far they are ubiquitously expressed, not membrane-bound and contain coiled coil domains required for constitutive activation of the ret tk domain. In the PTC6 rearrangement the ret tk domain is fused to the aminoterminal part of the human transcription intermediary factor htif 1. In the PTC7 rearrangement the ret tk domain is fused to a novel protein that is strongly related to htif1. Like htif1 it contains a RBCC motif (ring finger, B boxes, coiled coil domain) located in the aminoterminal part and a phd finger and a bromodomain in the carboxyterminal part. Htif1 and related proteins are transcription coactivators for nuclear receptors, thus participating in controlling cellular development, differentiation and homeostasis. This is the first report on their involvement in human thyroid carcinogenesis. (+info)
Relationship among 201T1 uptake, nuclear DNA content and clinical behavior in metastatic thyroid carcinoma.
(18/1566)
A prospective study of 201TI uptake was performed to compare 201TI uptake with nuclear deoxyribonucleic acid (DNA) content and clinical behavior of tumors in metastatic thyroid carcinoma and to assess the significance of 201TI uptake in evaluating clinical characteristics of thyroid carcinoma. METHODS: Fifty-six patients with metastases of differentiated thyroid carcinoma had 201TI scintigraphy. Grade of 201TI uptake was semiquantitatively assessed according to tumor-to-background ratio on 2-h late scan. Nuclear DNA content was analyzed within 3 wk of 201TI study by flow cytometry using biopsy material and was classified as diploidy or aneuploidy. Patients were followed up to examine incidence of tumor growth and/or anaplastic transformation. RESULTS: DNA content was diploidy in 48 patients and aneuploidy in 8 patients. 201TI uptake in the DNA-aneuploid group (2.61 +/- 0.29) was significantly higher than that in the DNA-diploid group (1.82 +/- 0.35, P < 0.01 for both groups). Tumor growth was observed in all patients with DNA aneuploidy but in only 5 of 48 patients with DNA diploidy (P < 0.01). Anaplastic transformation was observed in 3 patients in the DNA-aneuploid group but in none of the patients in the DNA-diploid group. CONCLUSION: High 201TI uptake indicates greater incidence of abnormal DNA content with aggressive clinical behavior of metastatic tumors. Thus, 201TI scintigraphy may be useful in characterizing metastatic thyroid carcinoma and in identifying those patients with poorer prognoses. (+info)
Value of FDG PET in papillary thyroid carcinoma with negative 131I whole-body scan.
(19/1566)
The management of metastatic thyroid carcinoma patients with a negative 131I scan presents considerable problems. Fifty-four athyrotic papillary thyroid carcinoma patients whose 1311 whole-body scans were negative underwent 18F-fluorodeoxyglucose (FDG) PET; the purpose was to determine whether this procedure could localize metastatic sites. We also assessed its usefulness in the management of these patients. METHODS: Whole-body emission scan was performed 60 min after the injection of 370-555 MBq 18F-FDG, and additional regional attenuation-corrected scans were obtained. Metastasis was pathologically confirmed in 12 patients and was confirmed in other patients by overall clinical evaluation of the findings of other imaging studies and of the subsequent clinical course. RESULTS: In 33 patients, tumor had metastasized, whereas 21 patients were in remission. FDG PET revealed metastases in 31 patients (sensitivity 93.9%), whereas thyroglobulin levels were elevated in 18 patients (sensitivity 54.5%). FDG PET was positive in 14 of 15 metastatic cancer patients with normal thyroglobulin levels. In 20 of 21 patients in remission, FDG PET was negative (specificity 95.2%), whereas thyroglobulin levels were normal in 16 patients (specificity 76.1%). The sensitivity and specificity of FDG PET were significantly higher than those of serum thyroglobulin. In patients with negative 1311 scans, FDG PET detected cervical lymph node metastasis in 87.9%, lung metastasis in 27.3%, mediastinal metastasis in 33.3% and bone metastasis in 9.1%. In contrast, among 117 patients with 131I scan-positive functional metastases, 131I scan detected cervical lymph node metastasis in 61.5%, lung metastasis in 56.4%, mediastinal metastasis in 22.2% and bone metastasis in 16.2%. In all 5 patients in whom thyroglobulin was false-negative with negative antithyroglobulin antibody, PET showed increased 18F-FDG uptake in cervical lymph nodes, mediastinal lymph nodes, or both. Among patients with increased 18F-FDG uptake only in the cervical lymph nodes, the nodes were dissected in 11. Metastasis was confirmed in all, even in normal-sized lymph nodes. CONCLUSION: FDG PET scan localized metastatic sites in 131I scan-negative thyroid carcinoma patients with high accuracy. In particular, it was superior to 131I whole-body scan and serum thyroglobulin measurement for detecting metastases to cervical lymph nodes. FDG PET was helpful for determining the surgical management of these patients. (+info)
RET proto-oncogene in the development of human cancer.
(20/1566)
The RET proto-oncogene, located on chromosome subband 10q11.2, encodes a receptor tyrosine kinase expressed in tissues and tumors derived from neural crest. Germline (present in every cell of the body) mutations in RET cause multiple endocrine neoplasia type 2 (MEN 2), an inherited cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PC), and hyperparathyroidism (HPT). This knowledge has allowed molecular diagnosis and presymptomatic DNA-based testing to become possible. RET testing is considered the standard of care in MEN 2 families because clinical decisions are made based on the results of such gene testing. There appears to be a correlation between specific RET mutation type and organ-specific tumor development. Such knowledge might be useful in tailoring targeted surveillance in the near future. Somatic (in the tumor only) RET mutations have been found in a proportion of sporadic MTCs and PCs. Whether the presence of somatic RET mutation is associated with a poor prognosis is currently being investigated as another tool for molecular medicine. (+info)
Effect of 22-oxa-1,25-dihydroxyvitamin D3 on human thyroid cancer cell growth.
(21/1566)
To examine whether synthetic vitamin D3 analog, 22-oxa-1,25(OH)2D3 (OCT) has an inhibitory effect on the growth of thyroid carcinoma, we tested the in vitro and in vivo effects of OCT on the growth of a well-differentiated thyroid cancer cell line, NPA. OCT bound to its receptor at the same rate as 1,25(OH)2D3, and inhibited the proliferation of NPA cells in vitro in a dose-dependent manner, similar to that observed with 1,25 (OH)2D3. Northern blot analysis showed that steady-state and fetal bovine serum-stimulated levels of c-myc mRNA were suppressed after 0.5-4 hour treatment with OCT. Transfection studies with the deletion mutants of the 5'-up-stream flanking region of c-myc/chloramphenicol acetyltransferase chimera genes indicated the presence of an OCT responsive element between -410 and -106. Next, we examined OCT effects in implanted NPA tumor cells in nude mice. OCT showed no remarkable hypercalcemic effect compared to 1, 25 (OH2)D3, but OCT and 1, 25 (OH2)D3, had no significant inhibitory effect in vivo after either intra-tumor or intra-peritoneum injection. Our results demonstrate that OCT inhibits the proliferation of well-differentiated thyroid cancer in an in vitro system associated with the suppression of c-myc mRNA, but this inhibitory effect was not reproducible in in vivo model. (+info)
Comparison of 99mTc-methoxyisobutyl isonitrile and 201Tl scintigraphy for detection of residual thyroid cancer after 131I ablative therapy.
(22/1566)
In this study, we compared 99mTc-methoxyisobutyl isonitrile (MIBI) with 201Tl scintigraphy for the detection of residual thyroid cancer not found by 131I scans in patients with increased risk of recurrence after 131I therapy. METHODS: 201Tl and MIBI scans were obtained in 54 patients with negative 131I scans 3-25 y (median 7.9 y) after the first postsurgical 131I therapy. Serum thyroglobulin (Tg) levels were measured while patients were receiving thyroid hormone and again 6 wk after withdrawal of hormone therapy. RESULTS: The overall results were the same for both 201Tl and MIBI imaging, with a sensitivity of 19 of 36 (53%), specificity of 17 of 17 (100%) and accuracy of 36 of 54 (69%). Planar images missed residual cancer in high cervical lymph nodes adjacent to salivary gland activity, in small nodes (<1 cm) deep in the neck or chest and with diffuse pulmonary micrometastases. Serum Tg was elevated in 24 of 36 (67%) patients with residual cancer; 201Tl detected tumor sites in 13 of 24 (54%) of these patients, and MIBI detected tumor sites in 14 of 24 (58%) of these patients. Of the 12 patients who had residual cancer and false-negative serum Tg levels, 6 had true-positive 201Tl and 5 had true-positive MIBI scans. CONCLUSION: 201Tl and MIBI planar imaging yield the same high specificity and positive predictive value for residual thyroid cancer in patients with high-risk profiles and negative radioiodide scans. Both imaging agents detected residual cancer in more than half of the patients in whom conventional staging techniques did not reliably detect either the presence or the extent of residual thyroid cancer and changed the management in patients with surgically resectable cancer. (+info)
Preoperative diagnosis of thyroid papillary and anaplastic carcinomas by real-time quantitative reverse transcription-polymerase chain reaction of oncofetal fibronectin messenger RNA.
(23/1566)
The restricted expression of oncofetal fibronectin (onfFN) mRNA in thyroid papillary and anaplastic carcinomas was recently reported. In this study, we measured the copy number of onfFN mRNA in RNAs extracted from fine needle aspiration biopsies by real-time quantitative reverse transcription-PCR using thyroglobulin mRNA as an internal control. By measuring the onfFN:thyroglobulin mRNA ratio, preoperative aspirates from 31 papillary carcinomas and an anaplastic carcinoma can be distinguished from those from 5 adenomatous goiters, 5 follicular adenomas, and 4 follicular carcinomas. Thus, quantification of onfFN by real-time quantitative reverse transcription-PCR may be useful for the preoperative diagnosis of papillary and anaplastic carcinomas. (+info)
Chromosomal imbalances in noninvasive papillary bladder neoplasms (pTa).
(24/1566)
Almost 70% of urinary bladder neoplasms present as low-grade papillary noninvasive tumors (stage pTa). To determine which genomic alterations can occur in pTa tumors of different grades and to evaluate the prognostic significance of chromosomal imbalances, we analyzed 113 pTa tumors (40 grade 1, 55 grade 2, 18 grade 3) by comparative genomic hybridization. pTaG1 (1.9 +/- 2.0) and pTaG2 (3.1 +/- 2.9) tumors had only few genomic alterations with 9q- (44%), 9p- (36%), and -Y (21%) being most prevalent. Neither the total number of aberrations nor any individual alteration was linked to the risk of recurrence in 95 pTaG1/G2 tumors with clinical follow-up information. pTaG3 tumors were characterized by a high number of alterations (7.7 +/- 4.5; P < 0.0001 for G3 versus G2). Several chromosomal imbalances that have previously been reported to be typical for invasive bladder neoplasms were significantly more frequent in pTaG3 than in pTaG2 tumors, including 2q-, 5p+, 5q-, 6q-, 8p-, 10q-, 18q-, and 20q+. A malfunction of genes at these loci may contribute to the development of high-grade urothelial neoplasias. However, there is no evidence for a direct role of these alterations for development of invasive tumor growth. (+info)