Somatic mutation of PTEN in bladder carcinoma

Abstract

SummaryThe tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (≥ pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23.

MMAC1/PTEN inhibits cell growth and induces chemosensitivity to doxorubicin in human bladder cancer cells

“…In bladder cancer, LOH of chromosome 10q is more frequent in muscle-invasive tumors (Sandberg and Berger, 1994;Cappellen et al, 1997;Cairns et al, 1998;Aveyard et al, 1999). The tumor suppressor gene MMAC1/PTEN has been mapped to 10q23, suggesting that inactivation of this gene may be involved in bladder cancer progression (Sandberg and Berger, 1994;Cappellen et al, 1997;Aveyard et al, 1999).…”

“…The tumor suppressor gene MMAC1/PTEN has been mapped to 10q23, suggesting that inactivation of this gene may be involved in bladder cancer progression (Sandberg and Berger, 1994;Cappellen et al, 1997;Aveyard et al, 1999). Inactivation of MMAC1/PTEN appears to be an early event in endometrial carcinogenesis (Maxwell et al, 1998;Levine et al, 1998).…”

“…We have previously demonstrated that gelsolin, a regulator of the actin cytoskeleton mapped to chromosome 9q33, acts as a tumor suppressor in human bladder cancer cell lines both in vitro and in vivo (Tanaka et al, 1995). Recently, LOH of chromosome 10q has also been reported in bladder cancer (Sandberg and Berger, 1994;Cappellen et al, 1997;Cairns et al, 1998;Aveyard et al, 1999). MMAC1/PTEN/TEP1 has been identi®ed as a tumor suppressor gene mapped to chromosome 10q23 (Steck et al, 1997;Li and Sun, 1997;, and somatic mutations or deletions of MMAC1/PTEN have been found in bladder cancer as well as glioblastoma, melanoma, and cancers of the prostate, breast, endometrium, lung and thyroid (Steck et al, 1997;Wang et al, 1997;Gulberg et al, 1997;Cairns et al, 1997;Rhei et al, 1997;Tashiro et al, 1997;Kim et al, 1998;Dahia et al, 1997;Sano et al, 1999).…”

Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway

“…46,47 In invasive UCC, PTEN is mutated or shows loss of heterozygosity (LOH) in up to 30% of cases, 9,48,49 whereas this number falls to 6.6% in superficial tumors (pTa/pT1). 42 One group actually reported reduced PTEN protein expression in 94% of advanced stage bladder cancer specimens, whereas only 42% of superficial tumors and 8% of carcinoma in situ (CIS) specimens had reduced PTEN expression. 30 Researchers have also found that PTEN status may be important in influencing response to treatment.…”

“…13,17,28,42 PTEN also functions to regulate chemotaxis and cell motility, mechanisms that promote tumor invasion. 9,43-45 As a result, it is not surprising that PTEN loss is associated with aggressive tumor growth, metastases, and worsened patient outcomes.…”