Novel mutations of the MET proto-oncogene in papillary renal carcinomas. (9/1566)

Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.  (+info)

DNA copy number changes in thyroid carcinoma. (10/1566)

The genetic changes leading to thyroid cancer are poorly characterized. We studied DNA copy number changes by comparative genomic hybridization (CGH) in 69 primary thyroid carcinomas. In papillary carcinoma, DNA copy number changes were rare (3 of 26, 12%). The changes were all gains, and they were associated with old age (P = 0.01) and the presence of cervical lymph node metastases at presentation (P = 0.08). DNA copy number changes were much more frequent in follicular carcinoma (16 of 20, 80%) than in papillary carcinoma (P < 0.0001), and follicular carcinomas had more often deletions (13/20 versus 0/26, P < 0.0001). Loss of chromosome 22 was common in follicular carcinoma (n = 7, 35%), it was more often seen in widely invasive than in minimally invasive follicular carcinoma (54% versus 0%, P = 0.04), and it was associated with old age at presentation (P = 0.01). In three of the four patients with follicular carcinoma who died of cancer, the tumor had loss of chromosome 22. DNA copy number changes were found in 5 (50%) of the 10 medullary carcinomas studied. Four of these five carcinomas had deletions, and in two of them there was deletion of chromosome 22. Eleven (85%) of the thirteen anaplastic carcinomas investigated had DNA copy number changes, of which five had deletions, and one had deletion of chromosome 22. The most common gains in anaplastic carcinoma were in chromosomes 7p (p22-pter, 31%), 8q (q22-qter, 23%), and 9q (q34-qter, 23%). We conclude that DNA copy number changes are frequent in follicular, medullary, and anaplastic thyroid carcinoma but rare in papillary carcinoma when studied by CGH. Loss of chromosome 22 is particularly common in follicular carcinoma, and it is associated with the widely invasive type.  (+info)

Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma. (11/1566)

Although many genetic alterations are known to be associated with human transitional cell carcinoma (TCC) of the urinary bladder, relatively little is known about the roles of these molecular defects, singular or in combination, in bladder tumorigenesis. We have developed a transgenic mouse model of bladder tumorigenesis using a 3.6-kb promoter of uroplakin II gene to drive the urotheliums-specific expression of oncogenes. In this study, we demonstrate that transgenic mice bearing a low copy number of SV40T transgene developed bladder carcinoma in situ (CIS), whereas those bearing high copies developed CIS as well as invasive and metastatic TCCs. These results indicate that the SV40T inactivation of p53 and retinoblastoma gene products, defects frequently found in human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our results also provide experimental proof that CIS is a precursor of invasive TCCs, thus supporting the concept of two distinct pathways of bladder tumorigenesis (papillary versus CIS/invasive TCC). This transgenic system can be used for the systematic dissection of the roles of individual or combinations of specific molecular events in bladder tumorigenesis.  (+info)

A case of extraadrenal pheochromocytoma associated with adrenal cortical nodular hyperplasia and papillary thyroid carcinoma. (12/1566)

A 64-year-old woman was admitted in November, 1996 for fluctuating blood pressure. There was multinodular goiter in her neck. High urine VMA and serum aldosterone were noted. Computed tomography showed an oval lesion in the left adrenal gland. Left adrenalectomy was performed and the pathology was proved to be adrenal cortical nodular hyperplasia. Fluctuating blood pressure and high urine VMA persisted after the operation. CT scan of the abdomen revealed a soft tissue mass in lower abdomen. The patient was admitted again in September, 1997. Laboratory examinations showed normal serum aldosterone, normal plasma renin activity and high urine VMA. Aspiration cytology of the thyroid gland disclosed papillary thyroid carcinoma. [131I]-metaiodobenzylguanidine image revealed a high uptake lesion in the right L-3 paravertebral area. Tumor excision and thyroidectomy were performed. The pathology was reported as extraadrenal pheochromocytoma and papillary thyroid carcinoma. Papillary thyroid carcinoma is rarely associated with pheochromocytoma. To our knowledge, this paper is the first report of a patient with extraadrenal pheochromocytoma associated with papillary thyroid carcinoma and adrenal cortical nodular hyperplasia.  (+info)

Prognostic variables of papillary thyroid carcinomas with local invasion. (13/1566)

To evaluate the significance of the extrathyroid extension (ETE) of papillary thyroid carcinoma at the time of diagnosis and the prognostic variables of patients, we retrospectively reviewed 1,013 thyroid cancer patients. Of the 741 papillary thyroid cancer patients, 466 (62.9%) were categorized in clinical stage I and 114 (15.4%) were categorized in clinical stage III. Of the 114 patients in clinical stage III, 81 were female (mean age 44.4 +/- 15.7 years) and 33 were male (mean age 46.9 +/- 18.1 years). Of the clinical stage III patients, 104 patients received post-operative radioactive iodide (131I) therapy while 22 patients received external radiotherapy in the neck and upper mediastinum area post-operatively. In the study, age, gender, 131I accumulated dose, post-operative serum thyroglobulin (Tg) levels, and survival rate were demonstrated to be statistically significant in the groups with no recurrence and recurrence after treatment. The average follow-up period of these patients was 6.0 years. During this follow-up period, 11 patients expired. Eight died of thyroid cancer (7.0%) and 3 died of intercurrent diseases including asthma, renal cell carcinoma and propranolol overdose. Four of the 8 patients (50%) died of airway obstruction due to cancer cell invasion. Another 4 died of distant metastases, including 2 patients with skull metastases and brain invasion. The 5- and 10-year survival rates were 0.981 and 0.956 in clinical stage I and 0.923 and 0.843 in clinical stage III, respectively. In conclusion, the survival rate of the ETE of papillary thyroid cancer was lower when compared with stage I, especially in older male patients with higher post-operative serum Tg levels.  (+info)

Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. (14/1566)

Although the mortality rate associated with papillary microcarcinoma (PMC) of the thyroid generally is very low, some patients present with bulky nodal metastasis or distant metastasis and have an unfavorable prognosis. We retrospectively reviewed clinical aspects, surgical treatment and outcome of 178 patients with PMC in an attempt to determine the prognostic factors. The cause-specific 10-year survival rate was 96%. Three of four patients who showed signs of distant metastasis during the postsurgical period died of the disease, and another died of local recurrence. The most significant prognostic factors were the presence of clinically apparent lymph-node metastasis and hoarseness due to recurrent nerve palsy at the time of diagnosis. All distant metastases and cancer-specific deaths occurred in the 30 patients with symptomatic PMC who had either cervical lymphadenopathy, recurrent laryngeal nerve palsy or both. The 148 patients who had neither symptom had a distinctly favorable outcome. Total thyroidectomy followed by radioactive iodine treatment did not improve the final outcome in patients with symptomatic PMC. We conclude that patients with asymptomatic PMC can expect a truly favorable outcome, but some of those with symptomatic PMC may fall within a high-risk group of patients who do not benefit from aggressive treatment.  (+info)

At least three genes account for familial papillary thyroid carcinoma: TCO and MNG1 excluded as susceptibility loci from a large Tasmanian family. (15/1566)

Recent studies have mapped two susceptibility loci which appear to account for familial multinodular goitre (MNG1) and a variant of familial papillary thyroid cancer (PTC), with associated multinodular goitre (TCO). A Tasmanian family (Tas1) has been identified with an autosomal dominant form of PTC. This study has examined the MNG1 and TCO loci to determine if they are similarly predisposing the Tas1 family to PTC. Linkage analysis using identical microsatellite markers described in the two previous studies was used to determine the significance of these loci in the Tasmanian family. The resultant LOD scores were sufficiently negative using multipoint parametric analysis to exclude these two loci from involvement in the Tasmanian family. In addition, six candidate genes, RET, TRK, MET, TSHR, APC and PTEN were also excluded as susceptibility genes in Tas1 by using microsatellites that are positioned in or in close proximity to these genes. These results suggest that there are at least three susceptibility genes that predispose families to familial PTC.  (+info)

Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. (16/1566)

Germline mutations of c-met oncogene at 7q31 have been detected in patients with hereditary papillary renal cell carcinoma. In addition, c-met mutations were shown to play a role in 13% of patients with papillary renal cell carcinoma and no family history of renal tumors. The histopathology of papillary renal cell carcinoma with c-met mutations has not been previously described. We analyzed the histopathology of 103 bilateral archival papillary renal cell carcinomas and 4 metastases in 29 patients from 6 hereditary papillary renal cell carcinoma families with germline c-met mutations and 6 papillary renal cell carcinomas with c-met mutations from 5 patients with no family history of renal tumors. Twenty-five sporadic renal tumors with prominent papillary architecture and without somatic c-met mutations were evaluated for comparison. All papillary renal cell carcinomas with c-met mutations were 75 to 100% papillary/tubulopapillary in architecture and showed chromophil basophilic, papillary renal cell carcinoma type 1 histology. Fuhrman nuclear grade 1-2 was seen in tumors from 23 patients, and nuclear grade 3 was observed focally in 8 patients. Seventeen patients had multiple papillary adenomas and microscopic papillary lesions in the surrounding renal parenchyma. Clear cells with intracytoplasmic lipid and glycogen were focally present in tumors of 94% papillary renal cell carcinoma patients. Clear cells of papillary renal cell carcinoma had small basophilic nuclei, and clear cell areas lacked a fine vascular network characteristic of conventional (clear) cell renal cell carcinoma. We conclude that papillary renal cell carcinoma patients with c-met mutations develop multiple, bilateral, papillary macroscopic and microscopic renal lesions. Renal tumors with c-met genotype show a distinctive papillary renal cell carcinoma type 1 phenotype and are genetically and histologically different from renal tumors seen in other hereditary renal syndromes and most sporadic renal tumors with papillary architecture. Although all hereditary and sporadic papillary renal cell carcinomas with c-met mutations share papillary renal cell carcinoma type 1 histology, not all type 1 sporadic papillary renal cell carcinomas harbor c-met mutations.  (+info)