title: Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer.
abstract: Patients with clinically insignificant prostate cancer remain a major over-treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTEN loss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTEN loss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Murphy
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Farhad
authors.initials: F
authors.lastname: Kosari
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: B Edgardo R Parilla
authors.initials: BE
authors.lastname: Castellar
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sarah H
authors.initials: SH
authors.lastname: Johnson
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Terra
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Faye R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Geoffrey C
authors.initials: GC
authors.lastname: Halling
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Janet L Schaefer
authors.initials: JL
authors.lastname: Klein
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Aqsa
authors.initials: A
authors.lastname: Nasir
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Bergstrahl
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Laureano J
authors.initials: LJ
authors.lastname: Rangel
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Sukov
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: George
authors.initials: G
authors.lastname: Vasmatzis
authors.affiliation: Biomarker Discovery Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Cheville
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D001707:Biopsy, Needle; D004252:DNA Mutational Analysis; D050939:Gene Fusion; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000032:analysis / Q000235:genetics*; D010641:Phenotype; D017354:Point Mutation; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human