PTENMutations in Endometrial Cancers with 10q LOH: Additional Evidence for the Involvement of Multiple Tumor Suppressors

Simpkins, Sally B.; Peiffer-Schneider, Stacia; Mutch, David G.; Gersell, Deborah J.; Goodfellow, Paul J.

doi:10.1006/gyno.1998.5208

Cited by 48 publications

(18 citation statements)

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“…Both PTEN and DMBT1 were only altered in 25 ± 30% of glioblastomas, and in a signi®cant number of tumors with heterozygous deletions of 10q, alterations in either PTEN or DMBT1 could not be found (Liu et al, 1997;Tohma et al, 1998;Maier et al, 1998;Somerville et al, 1998;von Deimling et al, 2000). This lack of mutations in these genes was also demonstrated for other tumors which show frequent loss of distal regions of 10q, such as carcinomas of the respiratory tract (Petersen et al, 2000), melanoma (Herbst et al, 1999), endometrial cancers (Simpkins et al, 1998), hepatocellular carcinomas (Fujiwara et al, 2000;Yeh et al, 2000) and prostate carcinoma (Dong et al, 1998). Since Northern blot analysis indicates that WDR11 is expressed in a wide variety of human tissues, it may be a target for inactivation in these tumors as well.…”

Section: Discussionmentioning

confidence: 93%

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

et al. 2001

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Section: Discussionmentioning

confidence: 93%

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

et al. 2001

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“…Furthermore, previous studies have reported frequent loss of heterozygosity at chromosome 10q23 in endometrial and thyroid cancers (Simpkins et al, 1998). This gene is considered to act as a tumour suppressor gene in the pathogenesis of multiple cancers for several reasons: (i) This gene is frequently mutated in tumours arising in patients with Cowden disease and the Bannayan-Zonana syndrome, which are both characterized as hereditary syndromes leading to multiple hamartomas in the case of Cowden disease and both exhibit an increased risk of developing breast, thyroid and skin cancer Lynch et al, 1997;Marsh et al, 1997;Nelen et al, 1997).…”

Section: Discussionmentioning

confidence: 97%

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

et al. 2002

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PTEN is a candidate tumour suppressor gene and frequently mutated in multiple cancers, however, not in pancreatic cancer.Recently, it has been demonstrated that PTEN expression is regulated by TGF-b1. Using TGF-b1 transgenic mice (n=7) and wildtype littermates (n=6), as well as pancreatic tissues obtained from organ donors (n=10) and patients with pancreatic cancer (n=10), we assessed the expression of PTEN by means of immunohistochemistry and semiquantitative PCR analysis. In addition, PANC-1 cells were treated with TGF-b1 in vitro and the levels of PTEN mRNA were determined in these cells. In human pancreatic cancers PTEN mRNA levels were significantly decreased (P50.05). In addition, in the pancreas of TGF-b1 transgenic mice the expression of PTEN was significantly reduced (P50.01), as compared to wildtype littermates and incubation of PANC-1 cells with TGF-b1 decreased PTEN mRNA levels after 24 h. Inasmuch as TGF-b1 decreases PTEN expression in human pancreatic cancer cells and human pancreatic cancers overexpress TGF-b1, the reduced expression of PTEN in pancreatic cancer may be mediated by TGF-b1 overexpression. Thus, although PTEN is not mutated in pancreatic cancers, the reduction of its expression may give pancreatic cancer cells an additional growth advantage.

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“…Mutations in the PTEN tumor suppressor gene have been detected in ϳ35 to 50% of sporadic human UECs [1][2][3][4] in several independent studies and in 83% in one study. 5 Moreover, mutations have been identified in 20% of noninvasive precursor lesions called hyperplasias 8,9 and in 55% in one study.…”

Section: Discussionmentioning

confidence: 99%

“…PTEN mutations have been detected in 35 to 83% and MI in 20 to 45% of UECs. [1][2][3][4][5][6][7] In addition, both alterations have also been detected in complex atypical hyperplasia (CAH), the direct precursor of UEC. 5,8,9 Together these findings implicate an important and early role for PTEN mutations and DNA mismatch repair (MMR) deficiency, detected as MI, in the pathogenesis of UEC.…”

mentioning

confidence: 99%

DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous Mice

Wang

Douglas

Lia

et al. 2002

The American Journal of Pathology

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PTEN mutation and microsatellite instability are two of the most common genetic alterations in uterine endometrioid carcinoma. Furthermore, previous studies have suggested an association between the two alterations, however the basis and consequence of the association is not understood. Recently it has been shown that 100% of female Pten ؉/؊ mice develop complex atypical hyperplasia by 32 weeks of age that progresses to endometrial carcinoma in ϳ20 to 25% of mice at 40 weeks. In an attempt to expand this mouse model of endometrial tumorigenesis and to further our understanding of the association between Pten mutations and DNA mismatch repair deficiency, we generated Pten heterozygous, Mlh1-null (mismatch repair deficient) mice. Significantly, the majority of Pten ؉/؊ /Mlh1 ؊/؊ mice developed polypoid lesions in the endometrium at 6 to 9 weeks of age. By 14 to 18 weeks, all of the double-mutant mice had lesions histologically similar to those seen in Pten ؉/؊ mice, and two of them exhibited invasive disease. Moreover, the frequency of loss of the wildtype Pten allele in the double-mutant mice at 14 to 18 weeks was similar to that seen in lesions from 40-week-old Pten ؉/؊ mice. Taken together, our results indicate that DNA mismatch repair deficiency can accelerate endometrial tumorigenesis in Pten heterozygous mice and suggests that loss of the wild-type Pten allele is involved in the development/progression of tumors in this setting. To date, the most common genetic alterations identified in uterine endometrioid carcinoma (UEC), the most prevalent type of endometrial cancer, are mutations in the PTEN tumor suppressor gene and the presence of a molecular phenotype called microsatellite instability (MI). PTEN mutations have been detected in 35 to 83% and MI in 20 to 45% of UECs. [1][2][3][4][5][6][7] In addition, both alterations have also been detected in complex atypical hyperplasia (CAH), the direct precursor of UEC. 5,8,9 Together these findings implicate an important and early role for PTEN mutations and DNA mismatch repair (MMR) deficiency, detected as MI, in the pathogenesis of UEC. Moreover, several studies have shown a statistically significant association between PTEN mutations and MI, 1-3,10,11 however the basis and consequence of this association remains unknown.In this and previous studies it has been shown that 100% of 32-week-old female mice lacking one wild-type copy of Pten spontaneously develop lesions that closely resemble CAH in humans. Of note, ϳ20 to 25% of mice at 40 weeks of age develop invasive carcinoma with morphological similarities to UEC. 12,13 To exploit this mouse model of endometrial tumorigenesis and to further our understanding of the association between Pten mutations and DNA MMR deficiency, we developed Pten ϩ/Ϫ / Mlh1 Ϫ/Ϫ double-mutant mice. Here we present data showing that DNA mismatch repair deficiency can accelerate endometrial tumorigenesis in Pten heterozygous mice and that it is associated with loss of the wild-type Pten allele. Materials and Methods MiceMale Pten hetero...

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PTENMutations in Endometrial Cancers with 10q LOH: Additional Evidence for the Involvement of Multiple Tumor Suppressors

Cited by 48 publications

References 0 publications

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

Reduced PTEN expression in the pancreas overexpressing transforming growth factor-beta 1

DNA Mismatch Repair Deficiency Accelerates Endometrial Tumorigenesis in Pten Heterozygous Mice

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