Allelic expression of p73 in human ovarian cancers

Codegoni, Anna Maria; Bertoni, Francesco; Patregnani, Cinzia; Marinetti, E.; D’Incalci, Maurizio; Broggini, Massimo

doi:10.1023/a:1008320609591

Cited by 14 publications

(7 citation statements)

References 17 publications

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“…Our results indicate that the p73 gene may be not the target of 1p36.3 LOH in parathyroid adenomas, although allelic loss of the p73 is present. A similar conclusion ruling out p73 as a target gene was reached in studies of ovarian adenocarcinoma that harbor frequent LOH at 1p36 (21,22).…”

Section: Discussionsupporting

confidence: 61%

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

et al. 2001

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Although 1p is one of the most common loci showing loss of heterozygosity (LOH) in primary parathyroid adenoma, fine mapping has not been previously examined. In this study, we analyzed LOH in 32 primary parathyroid adenomas using five microsatellite markers at 1p36 (proximal-D1S507-D1S450-D1S2893-D1S468-D1S243-distal). All cases were heterozygous for at least one marker. The frequency of LOH varied from 41.2% (D1S468) to 7.1% (D1S507) among the different markers. LOH was detected consistently in a group of nine adenomas (28.1%, 9/32). A single region (7 cM) showing a consistent LOH at 1p36.3 was obtained that was flanked distally by D1S468 and proximally by D1S2893. Because the p73 gene is localized within this region and acts as a tumor suppressor gene, we examined the possible involvement of p73 in the development of parathyroid tumor. Allelic loss of p73 was identified in four adenomas (25%, 4/16 informative cases) that were all from the group of the nine adenomas with LOH, but somatic mutation was not detected in the remaining allele. At the StyI polymorphism of Exon 2, four of the six adenomas with LOH at 1p36 were heterozygous and expressed the GC allele. Of the six heterozygous adenomas without LOH, 4 showed biallelic and 2 monoallelic expressions (GC allele). All adenomas mainly expressed the p73␣ isoform. p73 protein was observed in five of the six adenomas with LOH and in two of the six adenomas without LOH. There were no differences in p73 protein levels between the samples with and without LOH. In conclusion, a candidate gene for parathyroid tumorigenesis is present within a 7-cM region at 1p36.3, however p73 is unlikely to be the target of the LOH at 1p36.3. KEY WORDS: 1p36, Hyperparathyroidism, Loss of heterozygosity, Parathyroid neoplasia, p73. Mod Pathol 2001;14(4):273-278Parathyroid adenoma is one of the most common endocrine tumors, characterized by excessive secretion of parathyroid hormone (PTH) and enlargement of mostly one parathyroid gland. The molecular mechanism of parathyroid tumorigenesis is still poorly understood (1). MEN 1 gene abnormality has been found in only about 20% of the sporadic parathyroid adenomas. Cyclin D1/PTH gene rearrangement seems to be involved only in a small subset of these tumors, and p53 gene mutations also appear to be rare. To localize the gene responsible for parathyroid tumorigenesis, loss of heterozygosity (LOH) has been analyzed in various loci, and different frequencies of LOH have been identified (2, 3

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Section: Discussionsupporting

confidence: 61%

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

et al. 2001

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“…Point mutations or very small deletions cannot be excluded with certainty in our patient samples; however, somatic mutations of the p73 gene in ovarian carcinomas (Ng et al, 2000) and other types of neoplasm appear to be very rare (Ikawa et al, 1999; Mai et al, 1998; Shishikura et al, 1999; Takahashi et al, 1998; reviewed by Levrero et al, 2000). In addition, a study on a large series of ovarian cancers reported only 2 cases with loss of heterozygosity at the p73 gene locus and no differences in allelic expression (Codegoni et al, 1999). These negative data and reports on consistent over‐expression of p73 at the RNA and the protein levels (Mai et al, 1998; Takahashi et al, 1998), as well as in our work, rather point to an oncogenic role of p73 in cancer, which would certainly warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of p73 splice variants and protein in benign and malignant ovarian tumours

et al. 2000

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The p73 gene encodes a protein with substantial structural and functional similarities to the tumour‐suppressor p53. Alternative splicing of p73 mRNA leads to expression of 6 known RNA species and proteins (α, β, γ, δ, ϵ, ζ). We analysed the expression of these splice variants in ovarian adenocarcinoma by RT‐PCR followed by detection of amplicons with the Southern technique and by immunoblot in 32 malignant and benign epithelial ovarian tumour specimens and 3 ovarian adenocarcinoma cell lines (A2780, 2008, OVCAR‐3). p73α mRNA was expressed in all 17 ovarian cancer specimens, and 14 of 17 expressed at least 3 splice variants. In contrast, a different expression pattern was present in the ovarian adenomas: p73α was detected in 6 of 12 benign tumours, and only 1 adenoma expressed 3 splice variants. p73 protein was expressed in 9 of 16 ovarian cancer specimens, in all cell lines and in 1 of 3 borderline tumours. In contrast, none of 9 ovarian adenomas expressed detectable amounts of p73 protein. Expression of p73 mRNA and protein was not correlated with FIGO stage and histological grade, but we observed a significant correlation with over‐expression of p53 protein. In summary, epithelial ovarian cancers express a more complex p73 isoform pattern and higher levels of p73 mRNA and protein than ovarian adenomas. Int. J. Cancer 88:66–70, 2000. © 2000 Wiley‐Liss, Inc.

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“…More than 20 human genes have been reported to have a mononucleotide repeat (of at least 8 bp) in a coding region, and many of these have been observed to suffer mutation. The list of genes carrying a coding-mononucleotide repeat includes genes that perform functions critical for preventing cancer, such as DNA repair (RAD50, DNA-PKcs, hMSH3, hMSH6, and XPG) and regulation of cell proliferation, apoptosis, and tumor growth (TGF␤RII, IGFIIR, CHK-1, BAX, ICE, caspase-5, FLASH, Apaf-1, E2F-4, TCF-4, Apc, c-myb, MYCL, CtIP, and MLSN1) (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Many more human genes are at risk of suffering mutation due to mononucleotide repeat instability.…”

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confidence: 99%

“…Cells proficient in repair do not exhibit MSI-H, but evidence is accumulating suggesting that low-level instability can occur (24). A so-called lowmicrosatellite-instability phenotype has been reported in cells from tissues that are either inflamed or hyperplastic and in carcinogen-induced rat mammary tumors (10,14,25,26). In addition, changes were seen in somatic cell microsatellites of offspring of individuals exposed to radiation from the Chernobyl disaster (27).…”

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confidence: 99%

Modeling variation in tumors in vivo

Stringer

Larson

Fischer

et al. 2005

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

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Transgenic mice that allow mutant cells to be visualized in situ were used to study variation in tumors. These mice carry the G11 placental alkaline phosphatase (PLAP) transgene, a mutant allele rendered incapable of producing its enzyme product by a frameshift caused by insertion of a tract of G:C base pairs in a coding region. Spontaneous deletion of one G:C base pair from this tract restores gene function, and cells with PLAP activity can be detected histochemically. To study tumors, the G11 PLAP transgene was introduced into the polyoma virus middle T antigen mammary tumor model. Tumors in these mice exhibited up to 300 times more PLAP ؉ cells than normal tissues. PLAP ؉ cells were located throughout each tumor. Many of the PLAP ؉ cells were singlets, but clusters also were common, with one cluster containing >30,000 cells. Comparison of these data to simulations produced by computer models suggested that multiple factors were involved in generating mutant cells in tumors. Although genetic instability appeared to have occurred in most tumors, large clusters were much more common than expected based on instability alone.microsatellites ͉ mutation ͉ instability ͉ mouse

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Allelic expression of p73 in human ovarian cancers

Abstract: In comparisons of ovarian cancers and borderline tumors, no differences in allelic distribution and/or expression were found, suggesting that p73 does not play an important role in the pathogenesis and development of ovarian cancer.

Cited by 14 publications

References 17 publications

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

Frequent Loss of Heterozygosity at 1p36.3 and p73 Abnormality in Parathyroid Adenomas

Differential expression of p73 splice variants and protein in benign and malignant ovarian tumours

Modeling variation in tumors in vivo

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