Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Velickovic, Marija; Delahunt, Brett; McIver, Bryan; Grebe, Stefan K.

doi:10.1038/modpathol.3880551

Cited by 76 publications

(48 citation statements)

References 24 publications

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“…It was recently reported that loss of one copy of a gene without any alteration in the remaining wild-type allele, a phenomenon referred to as haploinsufficiency, may be sufficient to promote cancer in many instances. Such is the case with the PTEN gene in solid renal cell carcinomas (Velickovic et al, 2002), SMAD4 in gastric cancers (Xu et al, 2000;Maurice et al, 2001) and p27 in various other cancers (Fero et al, 1998;Philipp-Staheli et al, 2001). Our data raise the possibility that haploinsufficiency of PTC may be involved in early UC, at least in tumours with LOH of the PTC marker.…”

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confidence: 52%

Alteration of the PATCHED locus in superficial bladder cancer

et al. 2003

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Chromosome 9 alterations are the most frequently encountered cytologic anomalies in urothelial carcinoma (UC). We previously screened 139 low-stage UCs for loss of heterozygosity on chromosome 9, and identified five distinct regions likely to harbour tumour-suppressor genes. The present study focused on deletion mapping in the 9q22 region with 11 additional microsatellite markers. New deletions in the 9q22 region were found in five tumours. Deletion mapping allowed us to identify a 0.5 CM common minimal region of deletion between markers D9S280 and D9S1809, encompassing PATCHED (PTC), a gene identified as a tumour suppressor in basal cell carcinoma and in medulloblastoma. A marker located in the first intron of this gene showed the highest percentage of deletion (45%). cDNA sequencing in 15 tumours with deletion of PTC showed no mutation in the remaining allele. However, average expression of PTC mRNA measured by semiquantitative RT-PCR was significantly decreased in tumours with LOH in the 9q22 region, compared to normal urothelium (P ¼ 0.04), while it showed marked fluctuations in tumours without deletion. Our results suggest that the PTC gene is a putative suppressor at the 9q22 locus and that haploinsufficiency of this gene may be an early event in the development of papillary bladder tumours.

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confidence: 52%

Alteration of the PATCHED locus in superficial bladder cancer

et al. 2003

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“…37,38 Reduced PTEN protein expression has been found in a high frequency in RCC and is associated with PKB/Akt activation in ccRCC, but interestingly not in pRCC. 2,39 The collected data suggests that in ccRCC the PTEN directed regulation of the PI-3 kinase pathway is affected by both genetic aberrations in the PTEN gene and by DJ-1 gene expression levels.…”

Section: Discussionmentioning

confidence: 99%

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

Sitaram

Cairney

Grabowski

et al. 2009

Intl Journal of Cancer

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DJ-1 is as a novel regulator of the tumor suppressor PTEN with stimulatory effects on PI3K-AKT/PKB signaling, one possible target of which is cMyc. The catalytic unit of the telomerase complex, hTERT, can be activated at different levels, including transcriptionally by cMyc and through phosphorylation by AKT/PKB. The aim of the study was to analyze the putative signaling pathway encompassing DJ-1, cMyc and hTERT in a series of 176 renal cell carcinomas (RCC) and experimentally in cell lines. DJ-1 mRNA expression was significantly elevated in clear cell RCC (ccRCC) compared with in papillary RCC (pRCC; p 5 0.005) and kidney cortex tissue (p < 0.001). ccRCC and pRCC demonstrated higher cMyc RNA levels than in kidney cortex (p < 0.001 for both) as well as increased levels of hTERT RNA (p < 0.001 and p 5 0.011, respectively). DJ-1 was positively correlated to cMyc and hTERT in ccRCC (p < 0.001 and p 5 0.019, respectively), but not in pRCC, indicating that this pathway could have a functional significance in ccRCC. siRNA knock down of DJ-1 induced downregulation of cMyc and hTERT mRNA associated with decreased expression of pAKT and cMyc protein levels. hTERT promoter activity was upregulated after DJ-1 transfection and this upregulation was inhibited after mutation of the cMyc binding sites. These experimental data support the functional link among DJ-1, cMyc and hTERT expression as indicated in the tumor material. Neither DJ-1, cMyc nor hTERT mRNA levels were associated with proliferation (S-phase fraction), telomere length or prognosis in ccRCC. ' UICCKey words: renal cell carcinoma; DJ-1; cMyc; hTERT; telomere length; proliferation; prognosis Renal cell carcinoma (RCC) constitutes a heterogeneous group of tumors regarding cytogenetic aberrations, morphologic appearance and clinical outcome. The WHO classification identifies different morphologic subtypes of sporadic RCC including the three most common types, clear cell (ccRCC), papillary (pRCC) and chromophobe RCC. 1 Each entity shows characteristic cytogenetic abnormalities indicating essential differences between the RCC subtypes regarding the mechanisms leading to tumor development.The phosphatase tensin homologue deleted on chromosome 10 (PTEN) protein is a well known tumor suppressor acting as a negative regulator of the phosphoinositide-3 (PI-3)-kinase pathway including the downstream Protein Kinase B (PKB)/Akt protein. In RCC, an association between decreased PTEN expression and high PKB/Akt activation has been described. 2 A novel protein, DJ-1 (also called Cap1/RS/PARK7), has been proposed to be involved in tumorigenesis by negatively regulating PTEN. 3 DJ-1 was first described as a protein showing a cooperative transforming activity with H-Ras in mouse NIH3T3 cells. 4 Overexpression of DJ-1 has been reported in several malignancies, including breast and lung. 5,6 Further, DJ-1 mRNA expression levels seemed to be associated with survival in lung cancer 3 and elevated levels of circulating DJ-1 and anti-DJ-1 auto-antibodies were detected in breast cance...

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“…Activity of mTORC1 inhibitors, particularly temsirolimus, in renal cell cancer has raised the possibility that responders share a common molecular phenotype that renders these tumours dependent on mTOR for growth and/or survival. In renal cell cancer, PTEN gene expression has been shown to be downregulated in a large percentage of cases, presumably by epigenetic silencing (Brenner et al, 2002;Velickovic et al, 2002). In particular, lack of PTEN expression has been shown to be an independent negative prognostic factor for diseasespecific survival in patients with metastatic renal cell carcinoma (Kim et al, 2005).…”

Section: Differential Review Of Biological Effects Of Mtor Inhibitionmentioning

confidence: 99%

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

et al. 2008

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The proof of principle that a drug targeting mTOR can improve survival has been obtained recently from a large randomised trial using temsirolimus as a first-line therapy in patients with advanced poor prognostic renal cell carcinoma. Consistent data have recently shown the important role of the PI3K/AKT/mTOR signalling pathway in the regulation of crucial metabolic and mitotic functions of cancer cells and endothelial cells allowing a better understanding of the role of mTOR in controlling cancer cell proliferation and survival as well as tumour angiogenesis. As a result, rapamycin derivatives (rapalogues) that block mTOR/Raptor complex 1 were shown to exert direct antiproliferative effects against endometrial cancers, in which cancer cells frequently lose PTEN function as well as mantle cell lymphomas, in which cancer cell proliferation appears to be driven primarily by cyclin D1 overexpression. The overall antitumour effects of rapalogues in renal cell carcinoma appear to be more complex with tumour growth inhibition resulting from direct G1/S cell cycle blockage and/or apoptotic effects in carcinoma cells along with the inhibition of downstream signalling of the HIF1a-induced VEGF/VEGFR autocrine loop in endothelial cells shutting down the maintenance of tumour angiogenesis. Despite extensive cognitive researches, it is difficult to appraise which of those mechanisms is predominant in patients. This review focuses on mechanisms of action of rapalogues focusing on antitumour effects in patients with renal cell carcinoma.

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Intragenic PTEN/MMAC1 Loss of Heterozygosity in Conventional (Clear-Cell) Renal Cell Carcinoma is Associated with Poor Patient Prognosis

Cited by 76 publications

References 24 publications

Alteration of the PATCHED locus in superficial bladder cancer

Alteration of the PATCHED locus in superficial bladder cancer

The PTEN regulator DJ‐1 is associated with hTERT expression in clear cell renal cell carcinoma

mTORC1 inhibitors: is temsirolimus in renal cancer telling us how they really work?

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