Accumulated allelic losses in the development of invasive urothelial cancer

Habuchi, Tomonori; Ogawa, Osamu; Kakehi, Yoshiyuki; Ogura, Keiji; Koshiba, Masanori; Hamazaki, Shuji; Takahashi, Rei; Sugiyama, Taketoshi; Yoshida, Osamu

doi:10.1002/ijc.2910530409

Cited by 95 publications

(52 citation statements)

References 20 publications

(26 reference statements)

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“…Deletion of chromosome 10 has been observed in cytogenetic studies of bladder cancer (Sandberg 1994), mostly as monosomy but in some cases as speci®c deletion of 10q. Loss of heterozygosity on chromosome 10q has previously been reported in 5 ± 7% of bladder tumors (Knowles et al, 1994;Habuchi et al, 1993) and 29% of renal tumors in allelotype studies (Morita et al, 1991a).…”

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Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers

et al. 1998

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A new tumor suppressor gene PTEN/MMAC1 was recently isolated at chromosome 10q23 and found to be inactivated by point mutation or homozygous deletion in glioma, prostate and breast cancer. PTEN/MMAC1 was also identi®ed as the gene predisposing to Cowden disease, an autosomal dominant cancer predisposition syndrome associated with an increased risk of breast, skin and thyroid tumors and occasional cases of other cancers including bladder and renal cell carcinoma. We screened 345 urinary tract cancers by microsatellite analysis and found chromosome 10q to be deleted in 65 of 285 (23%) bladder and 15 of 60 (25%) renal cell cancers. We then screened the entire PTEN/MMAC1 coding region for mutation in 25 bladder and 15 renal cell primary tumors with deletion of chromosome 10q. Two somatic point mutations, a frameshift and a splicing variant, were found in the panel of bladder tumors while no mutation was observed in the renal cell carcinomas. To screen for homozygous deletion, we isolated two polymorphic microsatellite repeats from genomic BAC clones containing the PTEN/MMAC1 gene. Using these new informative markers, we identi®ed apparent retention at the gene locus indicative of homozygous deletion of PTEN/MMAC1 in four of 65 bladder and 0 of 15 renal cell tumors with LOH through chromosome 10q. Identi®cation of the second inactivation event in six bladder tumors with LOH of 10q implies that the PTEN/MMAC1 gene is occasionally involved in bladder tumorigenesis. However, the low frequency of biallelic inactivation suggests that either PTEN/MMAC1 is inactivated by other mechanisms or it is not the only target of chromosome 10q deletion in primary bladder and renal cell cancer.

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Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers

et al. 1998

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“…More than 60% of transitional cell carcinomas (TCC) of the bladder of all stages and grades show loss of heterozygosity (LOH) of chromosome 9. [1][2][3][4][5][6] Although many tumors have LOH on both arms of the chromosome, a significant number (ϳ10% of tumors overall) have a region of interstitial LOH of 9p. 7 Many such deletions are small and this has allowed the identification of a critical region at 9p21 that contains CDKN2B and CDKN2A/ARF.…”

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confidence: 99%

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Aveyard¹,

Knowles²

2004

The Journal of Molecular Diagnostics

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Many tumors have large homozygous deletions of the CDKN2A locus (encoding p14 ARF and p16) and of CDKN2B (p15). Our aim was to determine which gene is the major target in bladder cancer. We used quantitative real-time PCR (RTQ-PCR) to determine copy number of p15, of p14 ARF exon 1␤, and p16 exon 2 in 22 tumor cell lines and 83 bladder tumors, some of which had been assessed previously by duplex PCR. Titration experiments showed that homozygous deletion could be detected in the presence of up to 30% normal DNA. Results for cell lines were compatible with previous cytogenetic analyses. Ten cell lines and 32 tumors (38.5%) had homozygous deletion of at least one target. Thirteen tumors (15.7%) had deletion of all three targets. Two tumors had deletion of p14 ARF exon 1␤ alone and four of p16 exon 2 alone. RTQ-PCR detected more homozygous deletions than duplex PCR. Finally we used a multiplex ligation-dependent probe amplification kit to provide independent confirmation of results. We conclude that with appropriate controls RTQ-PCR is a sensitive and robust method to detect copy number changes in tumors even in the presence of contaminating normal cell DNA. More than 60% of transitional cell carcinomas (TCC) of the bladder of all stages and grades show loss of heterozygosity (LOH) of chromosome 9. 1-6 Although many tumors have LOH on both arms of the chromosome, a significant number (ϳ10% of tumors overall) have a region of interstitial LOH of 9p. 7 Many such deletions are small and this has allowed the identification of a critical region at 9p21 that contains CDKN2B and CDKN2A/ARF. These two loci encode three tumor suppressor genes, p15, p16, and p14 ARF , all of which are cyclin-dependent kinase inhibitors with key functions in cell cycle regulation. 8,9The CDKN2A locus encodes p16 and p14 ARF , both of which are capable of inducing cell cycle arrest. 10,11 p16 and p14 ARF have different first exons (1␣ and 1␤, respectively) approximately 13 kb apart, 12 giving rise to products in alternate reading frames with no homology at the protein level 13,14 (Figure 1). Exons 1␣, 2, and 3 encode p16, which induces G1 cell cycle arrest via the Rb pathway. Exons 1␤, 2, and 3 encode p14 ARF , which inhibits p53 degradation via binding to mdm2.The mechanism of CDKN2A/ARF inactivation in human cancers is somewhat tumor specific. Homozygous deletions at CDKN2A/9p21 are common in bladder tumors 6,15-17 and have been described in a variety of other sporadic tumors, including melanomas 18 and gliomas. 19 Pancreatic adenocarcinomas show inactivation of CDKN2A by either homozygous deletion or point mutation, 20 whereas esophageal tumors commonly show inactivation by point mutation. 21 A third mechanism of inactivation, transcriptional silencing by promoter hypermethylation, is commonly found in colorectal carcinoma. 22 Point mutations have only rarely been identified in bladder tumors 15,23,24 and promoter methylation, only infrequently. 25 Since the discovery of p14 ARF , 14 much interest has centered on the relative involvement of ...

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“…Cytogenetic and molecular studies have identified genetic alterations on chromosome 11p as one of the most frequent events during the progression of bladder cancer (Habuchi et al, 1993;Shaw and Knowles, 1995;Voorter et al, 1996;Gibas and Gibas, 1997). Deletion mapping has revealed a common region of deletion between D11S922 (11p15.5) and D11S569 (11p15.1-11p15.2), but it is not yet known which particular gene constitutes the relevant target.…”

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confidence: 99%

Decreased expression of p57KIP2 mRNA in human bladder cancer

Oya

Schulz

2000

Br J Cancer

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Summary To identify targets of genetic and epigenetic alterations on chromosome 11p15.5 in human bladder cancer, expression of the imprinted KIP2, IGF2 and H19 genes was studied by quantitative RT-PCR in 24 paired samples of urothelial carcinomas and morphologically normal mucosa obtained by cystectomy, and in bladder carcinoma cell lines. The most frequent alteration in tumour tissue was decreased expression of KIP2 identified in 9/24 (37%) specimens. Decreased IGF2 and H19 mRNA levels were found in five (21%) and three (13%) tumours, respectively. One tumour each overexpressed IGF2 and H19. Loss of H19 expression was only found associated with loss of KIP2 expression, whereas decreased expression of IGF2 mRNA occurred independently. Almost all bladder carcinoma cell lines showed significant changes in the expression of at least one gene with diminished expression of KIP2 mRNA as the most frequent alteration. IGF2 mRNA levels were diminished in several lines, but increased in others. The KIP2 gene could be an important target of genetic and epigenetic alterations in bladder cancer affecting the maternal chromosome 11p15.5. However, reminiscent of the situation in Wilms' tumours, expression of the IGF2 gene on the paternal chromosome can also be disturbed in bladder cancers.

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Accumulated allelic losses in the development of invasive urothelial cancer

Cited by 95 publications

References 20 publications

Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers

Point mutation and homozygous deletion of PTEN/MMAC1 in primary bladder cancers

Measurement of Relative Copy Number of CDKN2A/ARF and CDKN2B in Bladder Cancer by Real-Time Quantitative PCR and Multiplex Ligation-Dependent Probe Amplification

Decreased expression of p57KIP2 mRNA in human bladder cancer

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