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.
Our data suggest that PTEN mutation is observed in a subset of RCCs and that, especially in clear-cell RCCs, it occurs as a late-stage event and may contribute to the invasive and/or metastatic tumor phenotype.
This study was undertaken to determine the LOH at the PTEN/MMAC1 locus (chromosome band 10q23.3) and to search for gene mutations in 15 chromophobe, 50 conventional, and 10 papillary RCCs as well as in 10 renal oncocytomas.
We examined microdissected specimens from 80 conventional (clear cell) renal cell carcinomas (cRCC), 27 papillary renal cell carcinomas (pRCC), and 16 chromophobe renal cell carcinomas (chRCC) for loss of heterozygosity (LOH) at and around the PTEN/MMAC1 locus and for mutations in the PTEN/MMAC1 gene.
Other genes involved in regulating hypoxia-inducible factor [e.g. genes encoding carbonic anhydrase-IX and PTEN (phosphatase and tensin homolog)] were reported to be prognostically important in renal cell carcinoma.
We concluded that a strong expression of PTEN in renal cell cancer did not block the PI3K-mediated phosphorylation of Akt in the tumour specimens analysed.
The aims of the present study were to determine the expression patterns of Akt pathway parameters PI3K, phosphatase and tensin homolog (PTEN), phosphor-Akt (p-Akt) and their combination, for their possible prognostic value in renal cell carcinoma (RCC).
The mTOR pathway showed widespread activation in RCC metastases of various sites with strong correlation between different components of this signaling cascade (P<.0001), but without significant PTEN genomic deletion.
Furthermore, 19 of 20 advanced RCC showed somatic hypermethylation upstream of KILLIN, with the majority hypermethylated at more than one CpG island (13/19 vs. 3/23 with germline methylation, P < 0.0001). qRT-PCR revealed that methylation significantly downregulates KILLIN expression (P = 0.05), and demethylation treatment by 5-aza-2'deoxycytidine significantly increased KILLIN expression in all RCC cell lines while only increasing PTEN expression in one line.
Here, we have investigated the activity of PI 3-K and the expression of PTEN, p53, tuberin, p-mTOR, and p-p70S6K in both Eker rat RCC and human renal AML.
Another variant (rs701848) in the 3'UTR region of PTEN was associated with increased RCC risk (P = 0.014, OR = 1.45, 95%CI = 1.08-1.96, CC vs. TT); however, the association was not significant after adjusting for multiple comparisons.
Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.