Biomedical subjects

Janos Geli

Publications and source records attributed to Janos Geli.

5 recordsLinked to original sources

PubMed2006

Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH.

Pheochromocytoma is a predominantly sporadic neuroendocrine tumor derived from the adrenal medulla. Previous low resolution LOH and metaphase-CGH studies reported the loss of chromosomes 1p, 3q, 17p and 22q at various frequencies. However, the molecular mechanism(s) behind development of sporadic pheochromocytoma remains largely unknown. We have applied high-resolution tiling-path microarray-CGH with the primary aim to characterize copy number imbalances affecting chromosome 22 in 66 sporadic pheochromocytomas. We detected copy number alterations on 22q at a frequency of 44%. The predominant finding was monosomy 22 (30%), followed by terminal deletions in 8 samples (12%) and a single interstitial deletion. We further applied a chromosome 1 tiling-path array in 7 tumors with terminal deletions of 22q and found deletions of 1p in all cases. Our overall results suggest that at least 2 distinct regions on both 22q and 1p are important in the tumorigenesis of sporadic pheochromocytoma. A large proportion of pheochromocytomas also displayed indications of cellular heterogeneity. Our study is to our knowledge the first array-CGH study of sporadic pheochromocytoma. Future analysis of this tumor type should preferably be performed in the context of the entire human genome using genome-wide array-CGH, which is a superior methodological approach. Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.

Adult↗

PubMed2005

The Ras effector NORE1A is suppressed in follicular thyroid carcinomas with a PAX8-PPARgamma fusion.

CONTEXT: The Ras effector NORE1A (RASSF5A) is a putative tumor suppressor and is inactivated in several human cancers. NORE1A has not been studied in thyroid cancer. OBJECTIVE: The objective of this study was to investigate whether NORE1A is involved in follicular thyroid cancer (FTC) development. DESIGN: We analyzed NORE1A expression in 25 FTCs, eight follicular thyroid adenomas, and seven normal thyroid tissues by TaqMan quantitative RT-PCR. The results were evaluated in relation to RASSF1A expression, RAS mutations, and PAX8-PPARgamma fusions assessed in the same material. NORE1A promoter methylation was assessed by the combined bisulfite restriction endonuclease assay. RESULTS: Although the NORE1A mRNA levels of the majority of the tumors were similar to those in the normal controls, the cases harboring a PAX8-PPARgamma translocation (n = 6) exhibited dramatically reduced NORE1A expression (P < 0.001). In contrast, RAS mutations (n = 5) and NORE1A down-regulation were mutually exclusive. A significant reduction in the expression of the NORE1A homolog and the bona fide tumor suppressor gene RASSF1A was observed, but with weak correlation to the respective NORE1A values. No NORE1A promoter methylation was detected in the 32 thyroid tumors analyzed. CONCLUSIONS: Our experiments demonstrate the suppression of NORE1A, a known Ras effector, in PAX8-PPARgamma carrying FTCs.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Expression profiling of adrenocortical neoplasms suggests a molecular signature of malignancy.

BACKGROUND: Distinguishing between adrenocortical adenomas and carcinomas is often difficult. Our aim was to investigate the differences in transcriptional profiles between benign and malignant adrenocortical neoplasms using complementary DNA microarray techniques. METHODS: We studied 7 patients with adrenocortical carcinomas and 13 with adenomas. Histopathology was reviewed in all patients; clinical follow-up was at least 1 year. Hybridizations were performed in duplicate against RNA reference. Expression levels were analyzed in the R environment for statistical computing with the use of aroma, limma, statistics, and class packages. RESULTS: Transcriptional profiles were homogeneous among adenomas, while carcinomas were much more heterogeneous. Hierarchical clustering and self-organizing maps could separate clearly carcinomas from adenomas. Among genes that were most significantly upregulated in carcinomas were 2 ubiquitin-related genes (USP4 and UFD1L) and several insulinlike growth factor-related genes (IGF2, IGF2R, IGFBP3 and IGFBP6). Among genes that were most significantly downregulated in carcinomas were a cytokine gene (CXCL10), several genes related to cell metabolism (RARRES2, ALDH1A1, CYBRD1 and GSTA4), and the cadherin 2 gene (CDH2). CONCLUSIONS: Through the use of cDNA arrays, adrenocortical adenomas and carcinomas appear to be clearly distinguishable on the basis of their specific molecular signature. The biologic importance of the up- and downregulated genes is yet to be determined.

Adrenal Cortex Neoplasms↗

PubMed2005

Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas.

Pheochromocytomas and abdominal paragangliomas are rare catecholamine-producing tumours arising from neural crest-derived chromaffin cells. Frequent deletions of several distinct regions on the short arm of chromosome 1 suggest their involvement in the tumourigenesis process. The RIZ1 tumour suppressor encoded by the RIZ gene in 1p36.21 represents an attractive candidate target for the distal 1p deletions in these tumours. A panel of 18 pheochromocytomas (14 benign, and 4 malignant) and 11 abdominal paragangliomas (4 benign, and 7 malignant) were characterised for somatic deletions and mRNA expression status of RIZ1 using loss of heterozygosity (LOH) analysis and real-time quantitative PCR, respectively. Furthermore, we evaluated the methylation status of the RIZ1 promoter utilising methylation-specific PCR (MSP). Intragenic LOH at the RIZ locus was detected in 10 of 16 informative cases (62%), including 8 of 12 pheochromocytomas (67%) and 2 of 4 paragangliomas (50%). RIZ1 mRNA appeared to be significantly under-expressed in the tumour samples compared to normal adrenal controls (mean 0.6 vs. 1.0, p<0.001). This was not associated with RIZ1 promoter methylation in any of the samples, indicating that promoter hypermethylation is unlikely to be the underlying cause of the frequent expressional silencing. The recurrent inactivation of the tumour suppressor RIZ1 suggests that this event may be a significant contributing factor to tumour development in pheochromocytomas and abdominal paragangliomas.

Abdominal Neoplasms↗

PubMed2002

Artiodactyl IgD: the missing link.

IgD has been suggested to be a recently developed Ig class, only present in rodents and primates. However, in this paper the cow, sheep, and pig Ig delta genes have been identified and shown to be transcriptionally active. The deduced amino acid sequences from their cDNAs show that artiodactyl IgD H chains are structurally similar to human IgD, where the cow, sheep, and pig IgD H chain constant regions all contain three domains and a hinge region, sharing homologies of 43.6, 44, and 46.8% with their human counterpart, respectively. According to a phylogenetic analysis, the Cdelta gene appears to have been duplicated from the Cmu gene >300 million yr ago. The ruminant mu CH1 exon and its upstream region was again duplicated before the speciation of the cow and sheep, approximately 20 million yr ago, inserted upstream of the delta gene hinge regions, and later modified by gene conversion. A short Sdelta (switch delta) sequence resulting from the second duplication, is located immediately upstream of the bovine Cdelta gene and directs regular mu-delta class switch recombination in the cow. The presence of Cdelta genes in artiodactyls, possibly in most mammals, suggests that IgD may have some as yet unknown biological properties, distinct from those of IgM, conferring a survival advantage.

Amino Acid Sequence↗