Biomedical subjects

Oliver Gimm

Publications and source records attributed to Oliver Gimm.

43 records · Page 3Linked to original sources

PubMed2002

Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma.

Loss of heterozygosity of chromosome 3p21 is one of the most frequent alterations in solid tumors, including thyroid carcinomas. Recently, we have characterized the novel tumor suppressor gene RASSF1 located in this locus. The RASSF1A isoform is epigenetically inactivated in a variety of human primary tumors. In this study, we investigated the expression and methylation status of the RASSF1 gene in thyroid carcinoma. In nine thyroid cancer cell lines, the RASSF1A promoter CpG island was methylated completely, and expression was absent. Treatment of these cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycytidine reactivated the transcription of RASSF1A. The methylation status of the RASSF1A promoter was analyzed in 38 primary thyroid tumors, including 1 poorly differentiated thyroid carcinoma, 5 medullary thyroid carcinoma (MTC), 10 follicular thyroid carcinoma (FTC), 9 undifferentiated thyroid carcinoma (UTC), and 13 papillary thyroid carcinoma (PTC). In 71% of thyroid carcinomas, the RASSF1A CpG island was hypermethylated. Methylation frequency was higher in the aggressive forms of thyroid carcinoma and was found in 80% of MTC, in 78% of UTC, and in 70% of FTC, compared with 62% in the more benign PTC. RASSF1A inactivation was detected in all stages of thyroid carcinoma scored by Tumor-Node-Metastasis classification. Additionally, we analyzed the methylation frequency of the CpG island of cell cycle inhibitor p16(INK4a) in the same thyroid tumors. The p16 gene was inactivated in 56 and 25% of cell lines and primary tumors, respectively. p16 methylation was detected in 56% of UTC, 10% of FTC, and 25% of PTC but not in MTC. In UTC, which belongs to the most aggressive carcinomas in humans, the most common combined inactivation of RASSF1A and p16 was detected. In general, 90% of tumors with p16 inactivation were also silenced for RASSF1A expression. However, RASSF1A hypermethylation was detected three times more frequently in thyroid cancers. Thus, RASSF1A inactivation may play a crucial role in the malignancy of thyroid carcinoma.

Carcinoma↗

PubMed2002

Germ-line mutations in nonsyndromic pheochromocytoma.

BACKGROUND: The group of susceptibility genes for pheochromocytoma that included the proto-oncogene RET (associated with multiple endocrine neoplasia type 2 [MEN-2]) and the tumor-suppressor gene VHL (associated with von Hippel-Lindau disease) now also encompasses the newly identified genes for succinate dehydrogenase subunit D (SDHD) and succinate dehydrogenase subunit B (SDHB), which predispose carriers to pheochromocytomas and glomus tumors. We used molecular tools to classify a large cohort of patients with pheochromocytoma with respect to the presence or absence of mutations of one of these four genes and to investigate the relevance of genetic analyses to clinical practice. METHODS: Peripheral blood from unrelated, consenting registry patients with pheochromocytoma was tested for mutations of RET, VHL, SDHD, and SDHB. Clinical data at first presentation and follow-up were evaluated. RESULTS: Among 271 patients who presented with nonsyndromic pheochromocytoma and without a family history of the disease, 66 (24 percent) were found to have mutations (mean age, 25 years; 32 men and 34 women). Of these 66, 30 had mutations of VHL, 13 of RET, 11 of SDHD, and 12 of SDHB. Younger age, multifocal tumors, and extraadrenal tumors were significantly associated with the presence of a mutation. However, among the 66 patients who were positive for mutations, only 21 had multifocal pheochromocytoma. Twenty-three (35 percent) presented after the age of 30 years, and 17 (8 percent) after the age of 40. Sixty-one (92 percent) of the patients with mutations were identified solely by molecular testing of VHL, RET, SDHD, and SDHB; these patients had no associated signs and symptoms at presentation. CONCLUSIONS: Almost one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations; routine analysis for mutations of RET, VHL, SDHD, and SDHB is indicated to identify pheochromocytoma-associated syndromes that would otherwise be missed.

Adolescent↗

PubMed2002

Regulatory subunit type I-alpha of protein kinase A (PRKAR1A): a tumor-suppressor gene for sporadic thyroid cancer.

The tumor-suppressor gene encoding the cyclic AMP-dependent protein kinase A type I-alpha regulatory subunit PRKAR1A has been mapped to chromosome 17 (17q22-24) and is mutated in Carney complex, a familial neoplasia syndrome that is associated with thyroid tumors. Other genes implicated in cyclic nucleotide-dependent signaling have been investigated in thyroid tumorigenesis. We studied protein kinase A (PKA) activity in noninherited follicular thyroid adenomas and follicular, papillary, and undifferentiated (anaplastic) thyroid carcinomas. We then examined these and additional thyroid tumors for losses of the 17q22-24 PRKAR1A region, mutations of the PRKAR1A gene, and expression of its peptide product. Total PKA activity was markedly increased in carcinomas over that in adenomas, whereas the ratio of free vs. total PKA activity was decreased in cancer. Consistent with these findings, the 17q22-24 region was frequently lost in cancer but not in benign adenomas. A novel inactivating mutation of the PRKAR1A gene (leading to premature termination of the predicted protein) was found in an aggressive thyroid cancer. The tumor with PRKAR1A gene mutation, as well as the tumors with 17q allelic losses, showed decreased PRKAR1A expression by immunostaining. We conclude that PRKAR1A, the most abundant regulatory subunit of protein kinase A and a principal cyclic AMP-signaling modulator, acts as a tumor-suppressor gene in sporadic thyroid cancer. Published 2002 Wiley-Liss, Inc.

Adenoma↗

PubMed2002

First experiences in intraoperative neurostimulation of the recurrent laryngeal nerve during thyroid surgery of children and adolescents.

BACKGROUND: Intraoperative neurostimulation of the recurrent laryngeal nerve may reduce nerve palsy during thyroid surgery and is well established in adults. No data regarding the value of neuromonitoring during thyroid surgery in children have been available. METHODS: In a retrospective study, the authors analyzed all children who underwent surgery in our department since 1995. Neurostimulation was performed as electromyography of the vocal muscle using an electrical stimulation electrode for identification of the recurrent nerve. RESULTS: The authors performed thyroid resections in 97 children (mean, 11.1 years), 75 because of thyroid carcinoma. The recurrent nerve was identified in each patient. The neuromonitoring was used in 53 patients. Postoperatively, one temporary nerve palsy was identified in this group (1.89%). In the group of 44 nonstimulated patients, 2 temporary (4.55%) and one permanent nerve dysfunctions (2.27%) occurred. In all stimulated patients, the results of intraoperative neurostimulation were identical with the postoperative function of the vocal cords. CONCLUSIONS: The intraoperative neurostimulation of the recurrent laryngeal nerve is a safe and reliable procedure in children and adolescents. It may reduce nerve damage during thyroid surgery. The neuromonitoring of the recurrent nerve is of high prediction for the postoperative function of the vocal cords.

Adolescent↗

PubMed2002

RET proto-oncogene mutations affecting codon 790/791: A mild form of multiple endocrine neoplasia type 2A syndrome?

BACKGROUND: In patients with multiple endocrine neoplasia type 2A syndrome, prophylactic thyroidectomy is generally recommended at the age of 5 to 6 years. Whether this recommendation is justified for exon 13 mutations is unknown. METHODS: We analyzed the clinical data from 40 patients harboring RET codon 790/791 mutations (exon 13) who had been treated in 4 specialized centers. RESULTS: Mean age was 35.2 +/- 21.6 years (range, 5.1-69.0 years). Thirteen patients were index patients (mean age, 57.7 +/- 11.3 years), 27 patients were screening patients (mean age, 24.4 +/- 16.5 years). In the index group, pT-category was: T0, n = 2; T1, n = 6; T2, n = 2; T3, n = 1; and T4, n = 2. Lymph node metastases were found in 5 patients and distant metastases in 1 patient. Postoperatively, 69% of index patients were biochemically cured. In the screening group, pT-category was: T0, n = 19; T1, n = 7; and T2, n = 1. Lymph node metastases were found in 2 patients. Postoperatively, 93% of screening patients were biochemically cured. The youngest patient with medullary thyroid carcinoma was 13.8 years, the youngest patient with lymph node metastases was 46.4 years. CONCLUSIONS: Patients with RET codon 790/791 mutations seemed to have a less aggressive clinical course compared with patients with classic multiple endocrine neoplasia type 2A syndrome. Still, index patients had a lower biochemic cure rate in comparison with screening patients. Timely total thyroidectomy including lymph node dissection is warranted.

Adolescent↗

PubMed2002

Papillary thyroid carcinoma in patients with RET proto-oncogene germline mutation.

The occurrence of papillary thyroid carcinoma in patients with RET germline mutations has been described in only eight cases since 1993. We report three women with a RET germline mutation in exon 13 and 14, affecting codon 790, 791, and 804, respectively, who underwent prophylactic thyroidectomy at the age of 29, 39, and 24 years, respectively. Histologic examination revealed C-cell hyperplasia and a small medullary thyroid carcinoma in the first patient and no pathologic changes of the C-cells in either of the other patients. However, all patients had papillary thyroid carcinoma (PTC). Concerning the frequency of PTC in patients with RET germline mutations who underwent surgery at our center (n = 104), it was found in 9.1% of all patients with RET mutation in codon 790, 791, and 804 (n = 33) but in none of the 104 patients with RET germline mutations not affecting codon 790, 791, or 804 (p = 0.0015). Our data and the data from the literature suggest a possible pathogenesis of PTC caused by exon 13 and 14 RET mutations that affect the intracellular domain of the encoded protein. Further investigation is necessary to confirm a potential pathogenetic role of exon 13 and 14 RET mutations with regard to the development of PTC.

Adolescent↗

PubMed2002

Expression of telomerase genes in thyroid carcinoma.

Telomerase (T) is a ribonucleoprotein complex that includes the telomerase RNA component (hTR), telomerase associated protein (TP1) and the telomerase catalytic subunit (hTERT). Telomerase has been shown in stem cells and found to be activated in tumor tissues and immortalized cells. We wanted to test whether the expression of the telomerase complex subunits correlate with the enzyme activity in human thyroid tissue. Hence, we determined the expression of hTERT, hTR and TP1 mRNA by RT-PCR and compared the results to telomerase activity as detected by the telomeric repeat amplification protocol (TRAP) assay. Fifteen benign goiters (G), 11 follicular carcinomas (FTC) including 2 oncocytic follicular carcinomas (also called Hurthle cell carcinoma, oFTC), 12 papillary carcinomas (PTC) including 3 microcarcinomas (mPTC), and 12 undifferentiated anaplastic thyroid carcinomas (UTC) were investigated. Experienced pathologists performed histological and pTNM classification in each specimen. RT-PCR analysis revealed that TP1 was ubiquitously expressed in all G and carcinomas. hTR was expressed in 4 out of 15 G, in 2 out of 3 mPTC, in 5 out of 9 PTC, in 5 out of 9 FTC, in all oFTC and in 9 out of 12 UTC samples. Regarding all carcinomas, no statistically significant correlation was observed between hTR-expression and tumor stage, lymph node or distant metastasis. hTERT-expression was associated with malignancy and tumor stage. All mPTC and 13 out of 15 G did not express hTERT, whereas all samples of pT3-4 tumor stage of FTC, PTC, UTC and all oFTC were positive for hTERT. No telomerase activity could be detected in G. Telomerase activity in carcinoma was only measurable in tissues that expressed the catalytic subunit hTERT. Our data indicate that telomerase activity is up-regulated in neoplastic cells. In contrast to TP1 and hTR, hTERT and telomerase activity may be of help in identifying invasive tumors and may be additional markers for classification of benign goiter and malignant thyroid carcinoma.

Adenocarcinoma, Follicular↗