title: Novel, gross chromosomal alterations involving PTEN cooperate with allelic loss in prostate cancer.
abstract: There is increasing evidence that multiple chromosomal rearrangements occur in prostate cancer. PTEN loss is considered to be a key event in prostate carcinogenesis but the mechanisms of loss remain to be fully elucidated. We hypothesised that gross rearrangements may exist that cause disruption of the PTEN gene in the absence of genomic deletion. We therefore designed a novel fluorescence in situ hybridisation (FISH) assay with probes overlying regions 3' and 5' of PTEN and a third probe overlying the gene. We aimed to identify both genomic deletions and gross rearrangements of PTEN that would be overlooked by previously reported single-probe FISH assays. We proceeded to evaluate a tissue microarray with radical prostatectomy and trans-urethral resection of the prostate specimens from 187 patients. We identified PTEN genomic loss in 45/150 (30%) radical prostatectomy patients and 16/37 (43%) trans-urethral resection of the prostate patients. Importantly, our assay detected novel chromosomal alterations in the PTEN gene (characterised by splitting of FISH signals) in 13 tumours (6.9% of all prostate cancers; 21% of PTEN-lost cancers). All PTEN-rearranged tumours had genomic loss at the other allele and had no expression of PTEN by immunohistochemistry. PTEN-rearranged tumours were significantly more likely to have an underlying ERG rearrangement. Our assay differentiated loss of the probe overlying PTEN in isolation or in combination with either one of or both the probes overlying the 3' and 5' regions. This gave an indication of the size of genomic loss and we observed considerable inter-tumoural heterogeneity in the extent of genomic loss in PTEN-lost tumours. In summary, gross rearrangements of the PTEN locus occur in prostate cancer and can be detected by a 'break-apart' FISH assay. This observation could explain the absence of PTEN protein expression in a subgroup of tumours previously classified as having heterozygous genomic loss using single-probe traditional FISH assays.
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Alison H M
authors.initials: AH
authors.lastname: Reid
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
authors.forename: Daniel
authors.initials: D
authors.lastname: Brewer
authors.forename: Susana
authors.initials: S
authors.lastname: Miranda
authors.forename: Ruth
authors.initials: R
authors.lastname: Riisnaes
authors.forename: Jeremy
authors.initials: J
authors.lastname: Clark
authors.forename: Lucy
authors.initials: L
authors.lastname: Hylands
authors.forename: Sue
authors.initials: S
authors.lastname: Merson
authors.forename: Roy
authors.initials: R
authors.lastname: Vergis
authors.forename: Charles
authors.initials: C
authors.lastname: Jameson
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.forename: Karina Dalsgaard
authors.initials: KD
authors.lastname: Sørenson
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Colin S
authors.initials: CS
authors.lastname: Cooper
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D016009:Chi-Square Distribution; D002869:Chromosome Aberrations; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008131:London; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009664:Norway; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics*; D010641:Phenotype; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D013997:Time Factors; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human