title: Intracellular location of BRCA2 protein expression and prostate cancer progression in the Swedish Watchful Waiting Cohort.
abstract: Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, Public Health Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Tryggvi
authors.initials: T
authors.lastname: Thorgeirsson
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Jordahl
authors.affiliation: Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA 02215, USA, Department of Histopathology, St. James's Hospital Dublin, Dublin 8, Ireland, Trinity College Dublin, Dublin, Ireland.
authors.forename: Richard
authors.initials: R
authors.lastname: Flavin
authors.affiliation: Department of Medicine and the Meyers Primary Care Institute, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Mara Meyer
authors.initials: MM
authors.lastname: Epstein
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, "F. Addarii" Institute of Oncology and Transplantation Pathology, S.Orsola-Malpighi Hospital, Bologna University, 40126 Bologna, Italy.
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Fiorentino
authors.affiliation: Department of Urology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
authors.forename: Swen-Olof
authors.initials: SO
authors.lastname: Andersson
authors.affiliation: Department of Urology, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
authors.forename: Ove
authors.initials: O
authors.lastname: Andren
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Rider
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA, Institute for Precision Medicine of Weill Cornell Medical College and New York Presbyterian, New York, NY 10065, USA.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Mosquera
authors.affiliation: National University of Ireland, Shantalla Road, Galway, Ireland.
authors.forename: Helen
authors.initials: H
authors.lastname: Ingoldsby
authors.affiliation: Clinical Epidemiology and Biostatistics, Faculty of Medicine and Health, Örebro University, SE 701 82 Örebro, Sweden.
authors.forename: Katja
authors.initials: K
authors.lastname: Fall
authors.affiliation: Icelandic Cancer Registry, 105 Reykjavik, Iceland and Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland laufeyt@krabb.is.
authors.forename: Laufey
authors.initials: L
authors.lastname: Tryggvadottir
authors.affiliation: Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA, Public Health Sciences, University of Iceland, 101 Reykjavik, Iceland.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D024682:BRCA2 Protein / Q000032:analysis / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000032:analysis*; D016022:Case-Control Studies; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D046888:Tissue Array Analysis; D057832:Watchful Waiting
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor