PTEN genomic deletion is associated with p-Akt and AR signalling in poorer outcome, hormone refractory prostate cancer

• Published in: The Journal of pathology Vol. 218; no. 4; pp. 505 - 513
• Main Authors: Sircar, Kanishka, Yoshimoto, Maisa, Monzon, Federico A, Koumakpayi, Ismael H, Katz, Ruth L, Khanna, Abha, Alvarez, Karla, Chen, Guanyong, Darnel, Andrew D, Aprikian, Armen G, Saad, Fred, Bismar, Tarek A, Squire, Jeremy A
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2009; Wiley
• Subjects: Aged; Aged, 80 and over; AKT protein; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Antibodies; Bacterial artificial chromosomes; Biological and medical sciences; chromosome 10; Chromosomes, Human, Pair 10; copy number; DNA probes; FISH; Fluorescence in situ hybridization; Gene Deletion; Genome; genomics; Genotype; haploinsufficiency; Hormones; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Metastases; microarray; Middle Aged; Mortality; Nephrology. Urinary tract diseases; Oligonucleotide Array Sequence Analysis; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Phenotype; Polymorphism, Single Nucleotide; prognosis; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Proto-Oncogene Proteins c-akt - metabolism; PTEN; PTEN Phosphohydrolase - analysis; PTEN Phosphohydrolase - genetics; PTEN protein; Receptors, Androgen - metabolism; Signal transduction; Signal Transduction - genetics; Single-nucleotide polymorphism; Statistics, Nonparametric; Treatment Failure; Tumors of the urinary system; tumour suppressor gene; Urinary tract. Prostate gland; Prognosis; Prostate disease; Hormone therapy; PTEN; Urology; Signal transduction; Cancerology; Fluorescence in situ hybridization; Deletion; Genetics; PTEN Gene; Male genital diseases; Tumor suppressor gene; Human; Treatment resistance; Urinary system disease; Akt protein kinase; tumour suppressor gene; Malignant tumor; microarray; Androgen receptor; FISH; Molecular biology; Prostate cancer; Cancer; Hormonal receptor
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.2559

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. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.