Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Common fragile sites (CFS) are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells. Several have been shown to contain genes that span large genomic regions, such as FHIT (1.5 Mb), WWOX (1.0 Mb), GRID2 (1.36 Mb), PARK2 (1.3 Mb), and RORA (730 kb). These genes are frequently inactivated in multiple different cancers, and FHIT and WWOX are shown to function as tumor suppressors. The disabled-1 gene (DAB1) is one of the human homologs of the Drosophila disabled locus, which in mammals is involved in neuronal migration and lamination in the developing cerebral cortex. Mice DAB1 inactivation results in the neurological mutant Scrambler, having similarities to mice with the inactivation of PARK2 (Quaker), GRID2 (Lurcher), and RORA (Staggerer). We were interested in whether DAB1 was another large CFS gene that could have cancer development importance. We demonstrated here that the human DAB1 gene (spanning 1.25 Mb) mapped within FRA1B CFS region on chromosomal band 1p32.2. Real-time RT-PCR analysis revealed that the expression level of DAB1 was decreased in many human cancer samples, including primary tumor tissues and cancer-derived cell lines, from several different cancers, especially in brain and endometrial cancer. Additionally, the introduction of an over-expression DAB1 plasmid into two different cell lines, having insignificant endogenous DAB1 expression, resulted in decreased cell growth. In summary, DAB1 is another gene that resides within an unstable CFS region and might play a role in human tumorigenesis. These data may provide further linkage between neurological development and cancer.
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PMID:Disabled-1 is a large common fragile site gene, inactivated in multiple cancers. 1800 69

Loss of heterozygosity and chromosomal rearrangement of the WWOX gene, which is located at 16q23.3-24.1, have been detected in ovarian, breast, hepatocellular, and prostate carcinomas and in other neoplasias. This gene, which spans the common chromosomal fragile site 16D, contains 9 exons and encodes a 46 kDa WWOX protein that contains 414 amino acids. The evidence from cancer cell lines and primary tumor tissues suggests that WWOX is a tumor suppressor gene and that its inactivation contributes to cancer development. The results from studies of WWOX gene knockout cancer cells and a WWOX knockout mouse model partly confirm this hypothesis. The nature of the various proteins that the WWOX protein can interact with, such as c-Jun, TNF, p53, p73, AP-2 gamma, and E2F-1, suggests that WWOX plays a central role in tumor suppression through transcriptional repression and apoptosis, with its apoptotic function the more prominent of the two. However, there is not universal agreement that WWOX is a tumor suppressor gene. Further analysis is needed to reveal the true nature of WWOX.
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PMID:WWOX tumor suppressor gene. 1843 86

We applied whole-genome single-nucleotide polymorphism arrays to define a comprehensive genetic profile of 23 esophageal adenocarcinoma (EAC) primary tumor biopsies based on loss of heterozygosity (LOH) and DNA copy number changes. Alterations were common, averaging 97 (range, 23-208) per tumor. LOH and gains averaged 33 (range, 3-83) and 31 (range, 11-73) per tumor, respectively. Copy neutral LOH events averaged 27 (range, 7-57) per EAC. We noted 126 homozygous deletions (HD) across the EAC panel (range, 0-11 in individual tumors). Frequent HDs within FHIT (17 of 23), WWOX (8 of 23), and DMD (6 of 23) suggest a role for common fragile sites or genomic instability in EAC etiology. HDs were also noted for known tumor suppressor genes (TSG), including CDKN2A, CDKN2B, SMAD4, and GALR1, and identified PDE4D and MGC48628 as potentially novel TSGs. All tumors showed LOH for most of chromosome 17p, suggesting that TSGs other than TP53 may be targeted. Frequent gains were noted around MYC (13 of 23), BCL9 (12 of 23), CTAGE1 (14 of 23), and ZNF217 (12 of 23). Thus, we have confirmed previous reports indicating frequent changes to FHIT, CDKN2A, TP53, and MYC in EAC and identified additional genes of interest. Meta-analysis of previous genome-wide EAC studies together with the data presented here highlighted consistent regions of gain on 8q, 18q, and 20q and multiple LOH regions on 4q, 5q, 17p, and 18q, suggesting that more than one gene may be targeted on each of these chromosome arms. The focal gains and deletions documented here are a step toward identifying the key genes involved in EAC development.
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PMID:Genome-wide copy number analysis in esophageal adenocarcinoma using high-density single-nucleotide polymorphism arrays. 1851 75

The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease.
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PMID:Frequent attenuation of the WWOX tumor suppressor in osteosarcoma is associated with increased tumorigenicity and aberrant RUNX2 expression. 2053 Jun 75

A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY), and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs)/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found). A large number of focal copy number alterations (FCNAs) were detected, including homozygous deletions (HDs) targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements). Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.
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PMID:Novel near-diploid ovarian cancer cell line derived from a highly aneuploid metastatic ovarian tumor. 2878 62