Chromosomal instability predicts metastatic disease in patients with insulinomas

Jonkers, Y. M. H.; Claessen, Sandra; Perren, Aurel; Schmid, Sonja; Komminoth, Paul; Verhofstad, A.A.J.; Hofland, L. J.; Krijger, R.R. de; Slootweg, Pieter J.; Ramaekers, Frans C. S.; Speel, Ernst J. M.

doi:10.1677/erc.1.00960

Cited by 72 publications

(64 citation statements)

References 52 publications

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“…This may be due to the fact that not all deletions are picked up in CGH analysis due to its limitations in resolution. 23 The observed loss rate of 45% is in accordance with our previous work, where we found 31% loss in a series of 29 pheochromocytomas, and with LOH analyses performed by others, which showed loss rates between 18 and 24%. 5,18,27 In five pheochromocytomas (10%), gain of 17p was found in CGH, although copy number gain could only be confirmed in two instances by FISH analysis.…”

Section: Discussionsupporting

confidence: 92%

“…23 This approach uses differentially labelled tumor and 'reference' DNA, which are competitively hybridized to normal metaphase chromosomes. The ratio of the fluorescence intensities detected is indicative of the relative DNA copy number in tumor vs reference DNA.…”

Section: Cghmentioning

confidence: 99%

“…22,23 A combination of centromere 17 (p17H8) and a PAC probe containing the p53 gene on chromosome 17p13.1, labelled with digoxigenin and biotin, respectively, was used for hybridization. Digoxigenin was detected by sheep anti-digoxigenin fluorescein (Roche) and biotin by two layers of avidin-rhodamine connected by a biotinylated goat anti-avidin antibody (Vector).…”

Section: Fishmentioning

confidence: 99%

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Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

et al. 2008

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Genetic changes in the tumorigenesis of sporadic pheochromocytomas are poorly understood, and there are no good markers to discriminate benign from malignant pheochromocytomas. p53 is a tumor suppressor gene and aberrations in this gene are frequently found in many tumor types. The role of p53 in pheochromocytoma tumorigenesis is unclear, with some studies suggesting that p53 mutations can be used to discriminate benign from malignant pheochromocytomas while other studies do not find such an association. Because most of these investigations were hampered by small series of tumors and the use of varying methods, we have performed a comprehensive analysis of p53 aberrations in a large series of pheochromocytomas. Comparative genomic hybridization analysis of 31 benign and 20 malignant tumors showed loss of the p53 locus at chromosome 17p13.1 in 23/51 (45%) cases, and most of these results were confirmed by fluorescence in situ hybridization. Forty-three tumors, including the malignant tumors and the tumors with loss of the p53 locus, were analyzed for p53 mutations in exons 5-8, but none were found. Furthermore, p53 immunohistochemistry on 35 cases revealed strong nuclear p53 expression in only two pheochromocytoma metastases, all other tumors being negative. We conclude that, although there is frequent loss of the p53 locus on 17p, the p53 gene does not appear to play a major role in pheochromocytoma tumorigenesis.

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Section: Discussionsupporting

confidence: 92%

Section: Cghmentioning

confidence: 99%

Section: Fishmentioning

confidence: 99%

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Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

et al. 2008

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“…In metastasized ATC, the number of gains remains stable, while a significant increase of genomic losses is seen (Figure 1), indicating that loss of function mutations are involved in the process of tumor dissemination. For pancreatic endocrine neoplasms, similar observations concerning an increase of CIN in metastasized versus non-metastasized tumors were previously reported (Jonkers et al, 2005) Our data suggest a model of carcinoid development and progression in which mitotic infidelity causes CIN at an early stage. During tumor progression, especially chromosomal losses inactivate the functions of tumor suppressor genes and promote metastatic behaviour.…”

Section: Discussionsupporting

confidence: 89%

Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential

et al. 2009

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Pulmonary carcinoids are infrequent neoplasms of the lung that normally display a less aggressive biological behavior compared to small cell and non-small cell lung cancers. Approximately 15-25% of carcinoids, in particular atypical carcinoids, show lymph node metastasis and have a worse prognosis than their non-metastasized counterparts. To date, there is no morphological or molecular marker that may help to differentiate between carcinoids that metastasize and carcinoids of identical differentiation that show only local tumor growth. In this study, we analyzed 7 metastasized and 10 non-metastasized pulmonary carcinoids for chromosomal and microsatellite instability in order to determine whether microsatellite instability or chromosomal imbalances are associated with metastasis. Due to the rare occurrence of metastasized carcinoids we compared our results of chromosomal instability with the hitherto published comparative genomic hybridization (CGH) profiles of pulmonary carcinoids, for which information about the absence or presence of metastasis was available. While microsatellite instability was not detected we found chromosomal instability as a common event in pulmonary carcinoids with an increase of frequency and extent of chromosomal alterations in atypical and metastasized carcinoids. These findings are in accordance with the collected and herein compiled data of previous studies and indicate increasing numbers of chromosomal imbalances to play a role in the sequential process of tumor development and metastasis.

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“…Deletion 6q was associated with metastasis in insulinoma (42), and deletions 6q14 and 6q16-q23 have been reported as recurrent cytogenetic aberrations in OS (43,44). Likewise, previous studies have shown an association of deletion 8p with disease progression in hepatocellular carcinoma (45) and colon cancer (46).…”

Section: Discussionmentioning

confidence: 87%

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

Yen

Chen

et al. 2009

Int J Oncol

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Abstract. Five osteosarcoma (OS) cell lines, 37 OS tumors and 9 corresponding non-neoplastic samples were genotyped by Affymetrix 10 K 2.0 SNP array. Regions of high level amplification and homozygous deletion were identified and validated by quantitative PCR and FISH. Certain recurrent cytogenetic alterations were more frequent in recurrent/ metastatic than in primary OS. These included deletion of 6q14.1, 6q16.2-q22.31, and 8p23.2-p12, amplification of 8q21.12, 8q22.3-q24.3 and 17p12, and loss of heterozygosity (LOH) at 2q24.3-q31.2, 5q11.2, 6p21.31-p21.1, 6q14.1-q16.2, 8p22-p12, 9q22.1, 10q21.1-q22.1, 10q23.31-q24.1, 12q15-q21.1 and 21q21.2-q21.3. Most of the LOH calls were associated with deletion, but a subset of them was associated with normal or increased copy number (CN). A consensus 3q13.31 deletion localized to a region within the limbic systemassociated membrane protein (LSAMP) gene was also identified. The FISH evaluations demonstrated highlylocalized homozygous or heterozygous LSAMP deletions in 6 of 11 primary OS. qRT-PCR evaluations of the two major alternative LSAMP transcripts demonstrated reduced expression of 1b isoform transcript in each of three OS with LSAMP exon 1b deletion. Further, the 1a isoform transcripts in these same OS had either reduced expression or a premature termination codon in LSAMP exon 2. This SNP genotyping study identified chromosomal aberrations associated with disease progression in OS and disclosed LSAMP as a novel tumor suppressor gene in OS. The study also demonstrated that CN and LOH analyses were able to detect distinct subsets of genetic abnormalities in OS.

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Chromosomal instability predicts metastatic disease in patients with insulinomas

Cited by 72 publications

References 52 publications

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

Frequent loss of 17p, but no p53 mutations or protein overexpression in benign and malignant pheochromocytomas

Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential

Identification of chromosomal aberrations associated with disease progression and a novel 3q13.31 deletion involving LSAMP gene in osteosarcoma

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