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- Diep, CB, et al.
(författare)
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Genetic profiling of colorectal cancer liver metastases by combined comparative genomic hybridization and G-banding analysis
- 2003
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 36:2, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- The majority of genetic studies of colorectal carcinogenesis have focused on changes found in primary tumors. Despite the fact that liver metastases are a leading cause of colorectal cancer deaths, the molecular genetic basis of the advanced disease stages remains poorly understood. We performed comparative genomic hybridization (CGH) on 17 liver metastases from colorectal carcinomas and compared the quantitative profile with the qualitative profile previously obtained with chromosome banding. An average of 12.6 aberrations per tumor was found by CGH. Chromosome 18 and chromosome arms 4q, 8p, and 17p were most frequently lost, whereas chromosomes 7 and 20 and chromosome arms 6p, 8q, and 13q were most frequently gained. We compared the chromosome banding and CGH data after converting the karyotypes into net copy number gains and losses. Ten tumors showed agreement between the findings of the two techniques, whereas five tumors did not (in two cases, no mitotic cells were obtained for banding analysis). All five discordant cases had a "simple" abnormal or normal karyotype, but revealed multiple changes by CGH. A likely explanation for this discrepancy is that in vitro growth before G-banding selected against the cancer cells. Interestingly, by comparing the CGH profiles of the "complex" vs. the "simple"/normal karyotype groups, deletion of 8p and gain of 16q were seen more frequently in the former group. The liver metastases had the same aberrations as seen in primary colorectal carcinomas, summarized in a literature survey. However, these aberrations were seen more frequently in liver metastases, which may be attributable to increased genetic instability. (C) 2003 Wiley-Liss, Inc.
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- Kraggerud, SM, et al.
(författare)
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Alterations of the fragile histidine triad gene, FHIT, and its encoded products contribute to testicular germ cell tumorigenesis
- 2002
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Ingår i: Cancer Research. - 1538-7445. ; 62:2, s. 512-517
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Tidskriftsartikel (refereegranskat)abstract
- The fragile histidine triad (FHIT) gene, located within chromosome arm 3p, is a potential target for testicular tumorigenesis. In the present study, 62 primary testicular germ cell tumors were analyzed for allelic imbalance (AI) at 10 loci mapping to chromosome bands 3p14.1-21.1. Twenty-seven tumors (44%) showed AI at one or more 3p loci. The chromosome 3 copy number was evaluated by fluorescence in situ hybridization with centromere and p-telomere probes onto interphase nuclei from 22 of the tumors. Sixteen of these (73%) presented three or more signals of each probe in at least one-third of the nuclei. The combined fluorescence in situ hybridization and AI results indicated that tumors with AI at all loci, in most cases (five of six), reflected an increased chromosome copy number, whereas tumors presenting AI only at some loci reflected interstitial chromosomal changes. A smallest region of overlapping changes could be delineated from tumors showing interstitial chromosomal changes (n = 16). The smallest region of overlapping changes was flanked by D3S1312 and D3S1234 and included parts of FHIT. In the second part of this study, expression analyses of FHIT were performed. Transcripts of aberrant lengths were found in 7 of 17 (41%) analyzed tumors and were identified by sequencing as splice variants. Three different types of transcripts were found, and all lacked exon 3. Immunohistochemical staining showed reduced Fhit protein expression, compared with normal testicular tissue, in 62% (40 of 65) of the testicular germ cell tumors. Although we found a significant association between FHIT mRNA alterations and AI (P = 0.006), altered protein expression did not correlate with AI. The nonepithelial components of teratomas showed strong association with reduced Fhit protein compared with the epithelial component (P < 0.001). Interestingly, reduced Fhit expression seems to be associated with metastasis in the patient at the time of diagnosis, although the association was not statistically significant.
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- Skotheim, RI, et al.
(författare)
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Topoisomerase-II alpha is upregulated in malignant peripheral nerve sheath tumors and associated with clinical outcome
- 2003
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 21:24, s. 4586-4591
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To identify target genes of clinical significance for patients with malignant peripheral-nerve sheath tumor (MPNST), an aggressive cancer for which no consensus therapy exists. Materials and Methods: Biopsies and clinical data from 51 patients with MPNST were included in this study. Based on our previous research implicating chromosome arm 17q amplification in MPNST, we performed gene expression analyses of 14 MPNSTs using chromosome 17-specific cDNA microarrays. Copy numbers of selected gene probes and centromere probes were then determined by interphase fluorescence in situ hybridization in 16 MPNSTs. Finally, we generated a tissue microarray containing 79 samples from 44 MPNSTs, on which in situ protein expressions of candidate genes were examined and related to clinical end points. Results: Among several deregulated genes found by cDNA microarray analyses, topoisomerase IIalpha (TOP2A) was the most overexpressed gene in MPNSTs compared with benign neurofibromas. Excess copies of the TOP2A were also seen at the DNA level in 10 of 16 cases, and high expression of the TOP2A protein was seen in 83% of the tumors on the tissue microarray. The TOP2A-expressing tumors were associated with poor cancer-specific survival and presence of metastases. Conclusion: We have identified TOP2A as a target gene in MPNST, using a focused gene expression profiling followed by a DNA copy number evaluation and clinical validation of the encoded protein using a tissue microarray. This study is the first to suggest that TOP2A expression may be a predictive factor for adverse outcome in MPNST. (C) 2003 by American Society of Clinical Oncology.
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