title: PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer.
abstract: PTEN haploinsufficiency is common in hormone-sensitive prostate cancer, though the incidence of genomic deletion and its downstream effects have not been elucidated in clinical samples of hormone refractory prostate cancer (HRPC). Progression to androgen independence is pivotal in prostate cancer and mediated largely by the androgen receptor (AR). Since this process is distinct from metastatic progression, we examined alterations of the PTEN gene in locally advanced recurrent, non-metastatic human HRPC tissues. Retrospective analyses of PTEN deletion status were correlated with activated downstream phospho-Akt (p-Akt) pathway proteins and with the androgen receptor. The prevalence of PTEN genomic deletions in transurethral resection samples of 59 HRPC patients with known clinical outcome was assessed by four-colour FISH analyses. FISH was performed using six BAC clones spanning both flanking PTEN genomic regions and the PTEN gene locus, and a chromosome 10 centromeric probe. PTEN copy number was also evaluated in a subset of cases using single nucleotide polymorphism (SNP) arrays. In addition, the samples were immunostained with antibodies against p-Akt, p-mTOR, p-70S6, and AR. The PTEN gene was deleted in 77% of cases, with 25% showing homozygous deletions, 18% homozygous and hemizygous deletions, and 34% hemizygous deletions only. In a subset of the study group, SNP array analysis confirmed the FISH findings. PTEN genomic deletion was significantly correlated to the expression of downstream p-Akt (p < 0.0001), AR (p = 0.025), and to cancer-specific mortality (p = 0.039). PTEN deletion is common in HRPC, with bi-allelic loss correlating to disease-specific mortality and associated with Akt and AR deregulation.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, TX, USA.
authors.forename: Kanishka
authors.initials: K
authors.lastname: Sircar
authors.forename: Maisa
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Federico A
authors.initials: FA
authors.lastname: Monzon
authors.forename: Ismael H
authors.initials: IH
authors.lastname: Koumakpayi
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Katz
authors.forename: Abha
authors.initials: A
authors.lastname: Khanna
authors.forename: Karla
authors.initials: K
authors.lastname: Alvarez
authors.forename: Guanyong
authors.initials: G
authors.lastname: Chen
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Darnel
authors.forename: Armen G
authors.initials: AG
authors.lastname: Aprikian
authors.forename: Fred
authors.initials: F
authors.lastname: Saad
authors.forename: Tarek A
authors.initials: TA
authors.lastname: Bismar
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use; D002879:Chromosomes, Human, Pair 10; D017353:Gene Deletion; D016678:Genome; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D018709:Statistics, Nonparametric; D017211:Treatment Failure
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D011944:Receptors, Androgen; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human