Analysis of PTEN and the 10q23 region in primary prostate carcinomas

Abstract

Deletions involving chromosome 10q23 occur frequently in prostatic carcinomas. Recently, a novel tumour suppressor gene, PTEN, mapping to this interval, has been identi®ed. Mutation or deletion of PTEN has been observed in a proportion of prostate cancer cell lines; however, primary prostate carcinomas have not been studied. We have investigated the involvement of PTEN in primary prostatic adenocarcinomas using a panel of 51 matched normal and prostate tumour DNAs. We ®rst determined the proportion of tumours with allele loss at loci in 10q23 which span the region containing the PTEN gene. Our results show that LOH involving 10q23 is common in primary prostate carcinomas. Twenty-®ve of 51 (49%) tumours showed loss of heterozygosity (LOH) over the region spanning the PTEN locus. We next directly analysed the PTEN gene for mutations of the coding region using single strand conformation polymorphism (SSCP) and sequence analyses. Of those tumours with LOH, only a single tumour was found to carry a missense mutation in PTEN. No mutations in PTEN were identi®ed in tumours without LOH. Our results suggest either that mutation of PTEN is a late event in prostate tumorigenesis, or that another tumour suppressor gene important in prostate cancer may lie close to PTEN in 10q23.

Genome-wide analysis of allelic imbalance in prostate cancer using the Affymetrix 50K SNP mapping array

“…The results showed a set of genomic alterations characteristic to PCa, consisting of LOH and concomitant copy loss in large regions at chromosomes 6q, 8p, 10q, 13q and 16q. Most of these affected regions have previously been associated with PCa (Joos et al, 1995;Cooney et al, 1996;Elo et al, 1997;Feilotter et al, 1998;Hyytinen et al, 1999;Lin et al, 2004). However, the increase in resolution using high-density SNP arrays combined with laser microdissection enabled us to identify regions that have not previously been related to this disease, including a 2.9-Mb region showing LOH at chromosome 21q22.2 in 30% of the samples.…”

MYC oncogenes and human neoplastic disease

“…Suzuki et al (1998), in a study of advanced disease, were able to demonstrate either homozygous deletion or point mutations in metastatic lesions from 12 of 19 patients. In contrast, at least three studies, despite documenting 10q23 LOH, have either not con®rmed the presence of PTEN/MMAC1 point mutations or have observed them in only a very small fraction of tumors (Feilotter et al, 1998;Orikasa et al, 1998;Pesche et al, 1998). The clinical picture of individuals with Cowden disease, a familial cancer syndrome resulting from the inheritance of a mutant PTEN/ MMAC1 gene further contributes to the confusion.…”

The emerging role of the PI3-K-Akt pathway in prostate cancer progression

“…13,15,[93][94][95] Comprehensive surveys of various human cancers for PTEN deletion or mutation reveal that functional loss of PTEN frequently occurs in a wide spectrum of human cancers (reviewed in Vivanco and Sawyers, 2002 6 ). In prostate cancer, at least three mechanisms have been identified for functional loss of PTEN: chromosome deletion or loss of heterozygosity (LOH), [96][97][98][99][100][101] somatic mutations 95,[99][100][101][102][103] and epigenetic aberrations. 104,105 The majority of human prostate cancer cell lines and xenografts that have been evaluated show inactivation of the PTEN tumor-suppressor gene.…”