A novel 4 cM minimal deletion unit on chromosome 6q25.1-q25.2 associated with high grade invasive epithelial ovarian carcinomas

Colitti, Cristiano V.; Rodabaugh, Kerry J.; Welch, William R.; Berkowitz, Ross S.; Mok, Samuel C.

doi:10.1038/sj.onc.1201523

Cited by 38 publications

(24 citation statements)

References 17 publications

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“…LOH analysis of the long arm of chromosome 6 identified several regions of loss: 6q21-q23 (17), 6q25.1-q25.2 (18), and 6q25-q27 (6,19). Moreover, deletions at 6q27 are present in benign ovarian tumors (20), suggesting that alterations in one or more genes mapping to this region represent an early event in ovarian tumorigenesis.…”

mentioning

confidence: 99%

Parkin , a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27

Cesari

Martin

Calin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

291

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In an effort to identify tumor suppressor gene(s) associated with the frequent loss of heterozygosity observed on chromosome 6q25–q27, we constructed a contig derived from the sequences of bacterial artificial chromosome/P1 bacteriophage artificial chromosome clones defined by the genetic interval D6S1581–D6S1579–D6S305–D6S1599–D6S1008. Sequence analysis of this contig found it to contain eight known genes, including the complete genomic structure of the Parkin gene. Loss of heterozygosity (LOH) analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%). Both loci exhibited the highest frequencies of LOH in this study and are each located within the Parkin genomic structure. Whereas mutation analysis revealed no missense substitutions, expression of the Parkin gene appeared to be down-regulated or absent in the tumor biopsies and tumor cell lines examined. In addition, the identification of two truncating deletions in 3 of 20 ovarian tumor samples, as well as homozygous deletion of exon 2 in the lung adenocarcinoma cell lines Calu-3 and H-1573, supports the hypothesis that hemizygous or homozygous deletions are responsible for the abnormal expression of Parkin in these samples. These data suggest that the LOH observed at chromosome 6q25–q26 may contribute to the initiation and/or progression of cancer by inactivating or reducing the expression of the Parkin gene. Because Parkin maps to FRA6E , one of the most active common fragile sites in the human genome, it represents another example of a large tumor suppressor gene, like FHIT and WWOX , located at a common fragile site.

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mentioning

confidence: 99%

Parkin , a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27

Cesari

Martin

Calin

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

291

282

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“…Loss of heterozygosity (LOH) has been reported at high frequency in human ovarian cancer 28 in the 6q24 region where the putative tumor suppressor gene, ZAC is located. Mouse Zac1 is expressed strongly in many regions including lung, tongue, sclerotome and the periphery of pancreas.…”

Section: Expression Of Zac In Human Ovarymentioning

confidence: 99%

“…[23][24][25][26] Lot1 (Lost on transformation), the rat orthologue of ZAC, was cloned from rat ovarian surface epithelial cells transformed spontaneously in vitro 27 suggesting an association of ZAC with ovarian cancer. The frequent LOH of 6q24 in ovarian cancer 28 and some preliminary data 29 suggest that loss of ZAC expression may play a role in the initiation and/or progression of human ovarian cancer. In mice, imprinting of Zac1 may be regulated by a differentially methylated CpG island (DMR) that partially overlaps the Zac1 and Hymai genes.…”

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confidence: 99%

Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer

Kamikihara

Arima

Kato³

et al. 2005

Intl Journal of Cancer

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ZAC is a paternally expressed, imprinted gene located on chromosome 6q24, within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer (HOC). We have failed to identify genetic mutations in the ZAC gene in tumor material. Many imprinted genes contain differentially allele-specific-methylated regions (DMR) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by laser capture microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3, 8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC. (Supplementary material for this article can be found on the International Journal of Cancer website at

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“…Its expression is frequently down-regulated in the ovarian and breast carcinoma cells (1,5,6), and it is localized on chromosome 6q24 -25, a common site for loss of heterozygosity in many solid tumors (3,7). In addition, Lot1 is maternally imprinted, a mode of epigenetic control of gene expression levels that is common to many genes involved in growth control (8,9).…”

mentioning

confidence: 99%

Lot1 Is a Key Element of the Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/Cyclic AMP Pathway That Negatively Regulates Neuronal Precursor Proliferation

Fila

Trazzi

Crochemore

et al. 2009

Journal of Biological Chemistry

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A novel 4 cM minimal deletion unit on chromosome 6q25.1-q25.2 associated with high grade invasive epithelial ovarian carcinomas

Cited by 38 publications

References 17 publications

Parkin , a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27

Parkin , a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25–q27

Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer

Lot1 Is a Key Element of the Pituitary Adenylate Cyclase-activating Polypeptide (PACAP)/Cyclic AMP Pathway That Negatively Regulates Neuronal Precursor Proliferation

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