Molecular genetic alterations of FHIT and p53 genes in benign and malignant thyroid gland lesions (original) (raw)
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Journal of Clinical Investigation, 1993
The p53 gene was analyzed in tumor specimens obtained from 52 patients with various types of carcinoma of the thyroid gland by a combined molecular and immunocytochemical approach. The histologic types included 37 well-differentiated papillary and follicular carcinomas, 8 poorly differentiated, and 7 undifferentiated carcinomas. The p53 gene was shown to be unaffected in all differentiated tumors by single-strand conformation polymorphism analysis. However, in two out of eight (25%) of poorly differentiated carcinomas and five out of seven (71%) undifferentiated carcinomas, p53 mutations were identified and subsequently characterized by DNA sequencing. One undifferentiated carcinoma displayed two areas with varying degrees of differentiation. The comparative analysis of the p53 gene, in both the more and the less differentiated area of this tumor, clearly showed that the p53 mutation was confined to the latter component of the tumor specimen. These results indicate that mutations of the p53 gene are associated with the most aggressive histologic types of thyroid tumors, such as the undifferentiated carcinoma and, to a certain extent, the poorly differentiated carcinoma, and that the alterations of this gene represent a late genetic event in human thyroid carcinogenesis. (J. Clin. Invest. 1993.91:1753-1760 Key words: immunocytochemistry * polymerase chain reaction * single-strand conformation polymorphismtumor progressiontumor suppressor gene Address reprint requests to Dr.
Significance of P53 in human thyroid tumors
World Journal of Surgery, 1994
Mutational changes in the p53 tumor suppressor gene are the most frequent genetic alterations in human malignant tumors. Studies have shown a correlation of p53 expression in breast cancer with tumor prognosis. In contrast to mutational activation of ras and GSP in thyroid tumors, little is known about the role of p53 in thyroid tumor development. Therefore thyroid tumors and thyroid tumor cell lines were studied for the presence of p53 mutations. Snap-frozen tissues from 57 differentiated thyroid carcinomas (DTCs) and 5 goiters were studied by immunohistochemical methods. A panel of six antibodies (pAb 240, 421, 1620, 1801, DO7, and CM1) was employed by using the ABC technique. Five cell lines from DTCs (FTC133, 236, 238, PTC337, MTC164) were examined by the same technique. Additionally, genomic DNA from the cells was amplified by the polymerase chain reaction (PCR) and the PCR product studied for p53 mutations (R273H) by mutation-specific oligonucleotide hybridization (MOH) and temperature gradient gel electrophoresis (TGGE) for the p53 exon 8. None of the benign thyroid tumors and 7 of 57 (12%) DTCs strongly express p53 with a heterogeneous distribution in the tumor tissue. All seven patients have metastatic disease or dedifferentiated tumors G3 (three of seven). CM1 was positive in two cell lines (FTC-133, PTC-337), questionable in FTC-238, and negative in FTC-236 and MTC-164. All three follicular cell lines, however, and the original tumor tissue showed the same p53 mutation (R273H) in MOH analysis and TGGE. P53 mutations are rare in thyroid tumors, but the presence of p53 mutations indicates a poor prognosis. TGGE seems to be a sensitive method for detecting p53 mutations (1% sensitivity) and might play a role in tumor screening in the future.
p53 in a Thyroid Follicular Carcinoma with Foci of Poorly Differentiated and Anaplastic Carcinoma
Pathology - Research and Practice, 1996
The clinical and pathologic features of a rare case of follicular carcinoma with small foci of poorly differentiated and anaplastic carcinoma are presented. Eight years after the removal of the primary neoplasm, the patient developed pulmonary and brain metastases that were predominantly composed of the poorly differentiated and anaplastic components. A comparative immunohistochemical and molecular analysis of p53 status in the follicular, poorly differentiated and anaplastic components of the tumor was performed. p53 immunostaining was restricted to the poorly differentiated and anaplastic areas. Single strand conformation polymorphism analysis (SSCP-PCR) from DNA obtained by microdissection demonstrated the presence of a mutation (TAT-+ TGT; Tyr-+ Cys) in codon 220, exon six of the p53 gene in the anaplastic component, that was absent in the well-differentiated follicular areas. The results of that study in this rare tumor support that p53 has a tumor progression role in thyroid tumorigenesis.
International Journal of Cancer, 2008
Defective DNA damage response (DDR) can result in genomic instability (GIN) and lead to the transformation into cancer. P53-binding protein 1 (53BP1) belongs to a family of evolutionarily conserved DDR proteins. Because 53BP1 molecules localize at the sites of DNA double strand breaks (DSBs) and rapidly form nuclear foci, the presence of 53BP1 foci can be considered as a cytologic marker for endogenous DSBs reflecting GIN. Although it has been proposed that GIN has a crucial role in the progression of thyroid neoplasms, the significance of GIN during thyroid tumorigenesis remains unclear, particularly in patients. We analyzed, therefore, the level of GIN, as detected with immunofluorescence of 53BP1, in 40 cases of resected thyroid tissues. This study demonstrated a number of nuclear 53BP1 foci in thyroid cancers, suggesting a constitutive activation of DDR in thyroid cancer cells. Because follicular adenoma also showed a few 53BP1 nuclear foci, GIN might be induced at a precancerous stage of thyroid tumorigenesis. Furthermore, high-grade thyroid cancers prominently exhibited an intense and heterogeneous nuclear staining of 53BP1 immunoreactivity, which was also observed in radiation-associated cancers and in mouse colonic crypts as a delayed response to a high dose ionizing radiation, suggesting increased GIN with progression of cancer. Thus, the present study demonstrated a difference in the staining pattern of 53BP1 during thyroid carcinogenesis. We propose that immunofluorescence analysis of 53BP1 expression can be a useful tool to estimate the level of GIN and, simultaneously, the malignant potency of human thyroid tumors. © 2007 Wiley-Liss, Inc.
Journal of B.U.ON. : official journal of the Balkan Union of Oncology
Thyroid tumors of uncertain malignant potential (TT-UMP) constitute a relatively new diagnosis. The purpose of this study was to analyze the relationship between immunohistochemical panels, prognostic parameters and TT-UMP. Group I was composed of patients diagnosed as differentiated thyroid carcinoma (DTC) and Group II of patients diagnosed as TT-UMP. The prognostic scores of patients were calculated using data according to the well-known prognostic scoring systems MACIS, AMES, AGES. Evaluations of antibodies were based on the presence of nuclear staining for p16 and p53, membranous and cytoplasmic staining for epidermal growth factor receptor (EGFR) and cytoplasmic staining for fragile histidine triad (FHIT). Statistically significant difference was noted (p< 0.05) between Group I and Group II according to MACIS and AMES. No statistical difference was found in terms of immunostaining between groups when stained with p16, p53 and FHIT. On the other hand, in Group II a moderate p...
Endocrine Pathology, 1997
Molecular analyses of thyroid tumors have documented mutations in the tumor suppressor p53 gene almost exclusively in anaplastic carcinomas. In contrast, immunohistochemistry has localized p53 in differentiated papillary and follicular thyroid cancers. To establish the significance of p53 immunolocalization in these lesions, 78 thyroid tumors of follicular derivation were examined. All tumors were classified by strict criteria and the extent of tumor was determined morphologically. Immunohistochemical staining for p53 was performed on paraffin sections of formalin-fixed tumor tissue. The results of staining were correlated with diagnosis, tumor extent and clinical outcome. Immunopositivity for p53 was diffuse and strong in all five anaplastic carcinomas examined. There was no staining in five of six follicular adenomas. Four of nine follicular carcinomas had some degree of nuclear staining, but this was focal; all nine tumors were confined to the thyroid at the time of examination. Of 49 papillary carcinomas, 26 were intrathyroida[, and 7 of these were occult; there was no p53 positivity in any occult lesion and only 5 of the 19 palpable lesions stained. In contrast, among 23 papillary carcinomas with extrathyroidal extension or metastases, only 9 were negative for p53 immunoreactivity. Five of seven tall cell papillary carcinomas and one of two insular carcinomas had p53 immunopositivity and this correlated with aggressive behavior. These resuRs support the tumorigenic role of p53 mutations postulated for anaplastic thyroid carcinomas and indicate that localization of p53 by immunohistochemistry is a useful prognostic index of clinical behavior in differentiated thyroid carcinomas of follicular cell derivation.
P53 is an independent prognostic factor for survival in thyroid cancer
Anticancer research
p53 has been reported to be of prognostic importance in different types of cancer. Immunohistochemical measurement of p53 antigen activity could be a prognostic marker for aggressiveness and survival in thyroid cancer. Different types of antibodies have been used to detect p53 in previous studies without direct comparison to each other. A series of 54 patients with thyroid cancer who had undergone thyroidectomy between 1993 and 1998 is reported. All samples were chosen retrospectively and classified by routine histopathology, followed by immunohistopathological examination with three different types of antibodies (PAb1801, CM1 and DO-7) with the peroxidase method. Survival data was generated. The mean time of follow-up was 9.0 years. Eighteen patients died. Twenty-three (42.6%) samples were positive for p53 using the antibody PAb1801, 17 (31.5%) with using CM1 and only 4 (7.4%) cases with DO-7. Statistical analysis determined that the size (p = 0.02) and classification of the tumor ...
Oncogene, 1997
Alterations of the tumor suppressor gene p53 are uncommon in dierentiated thyroid neoplasia but are detected at high frequency in anaplastic thyroid carcinoma suggesting that impaired p53 function may contribute to the undierentiated and highly aggressive phenotype of these tumors. Eects of wild type p53 (wt-p53) re-expression were investigated in a human anaplastic thyroid carcinoma cell line (ARO) expressing a mutated p53. ARO cells were stably transfected with the temperature-sensitive p53 Val 135 gene (ts-p53) which exhibits wild type-like activity at 328C. Exogenous wt-p53 function in ARO-tsp53 clones was assessed by evaluating its transcriptional activity on a CAT reporter vector containing p53 binding sites. At 328C, a signi®cant reduction in the proliferation rate (%50%) was observed, with accumulation of cells in the G 0 /G 1 phase of the cell cycle. This eect was accompanied by induction of the expression of the growth inhibitor p21/ Waf1 gene. At 328C, ARO-tsp53 clones also showed a marked impairment of their tumorigenic potential. Furthermore, transfected clones re-acquired the ability to respond to thyrotropin (TSH) stimulation showing an increased expression of thyroid-speci®c genes (thyroglobulin, thyroperoxidase and TSH receptor). In conclusion, re-expression of wt-p53 activity in ARO cells, inhibits cell proliferation and restores responsiveness to physiological stimuli.