title: A molecular correlate to the Gleason grading system for prostate adenocarcinoma.
abstract: Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17 beta4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: True
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.forename: Sarah
authors.initials: S
authors.lastname: Hawley
authors.forename: Ching-Ying
authors.initials: CY
authors.lastname: Huang
authors.forename: David
authors.initials: D
authors.lastname: Gifford
authors.forename: Roger
authors.initials: R
authors.lastname: Coleman
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.forename: Edward
authors.initials: E
authors.lastname: Gelmann
authors.forename: Milton
authors.initials: M
authors.lastname: Datta
authors.forename: Elahe
authors.initials: E
authors.lastname: Mostaghel
authors.forename: Beatrice
authors.initials: B
authors.lastname: Knudsen
authors.forename: Paul
authors.initials: P
authors.lastname: Lange
authors.forename: Robert
authors.initials: R
authors.lastname: Vessella
authors.forename: Daniel
authors.initials: D
authors.lastname: Lin
authors.forename: Leroy
authors.initials: L
authors.lastname: Hood
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009367:Neoplasm Staging; D011471:Prostatic Neoplasms / Q000145:classification / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor