A molecular correlate to the Gleason grading system for prostate adenocarcinoma

Lawrence True, Ilsa Coleman, Sarah Hawley, Ching Ying Huang, David Gifford, Roger Coleman, Tomasz M. Beer, Edward Gelmann, Milton Datta, Elahe Mostaghel, Beatrice Knudsen, Paul Lange, Robert Vessella, Daniel Lin, Leroy Hood, Peter S. Nelson

    Research output: Contribution to journalArticle

    198 Scopus citations

    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 HSD17β4 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.

    Original languageEnglish (US)
    Pages (from-to)10991-10996
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume103
    Issue number29
    DOIs
    StatePublished - Jul 18 2006

    Keywords

    • Carcinoma
    • Expression profile
    • Microarray
    • Monoamine oxidase A

    ASJC Scopus subject areas

    • General

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  • Cite this

    True, L., Coleman, I., Hawley, S., Huang, C. Y., Gifford, D., Coleman, R., Beer, T. M., Gelmann, E., Datta, M., Mostaghel, E., Knudsen, B., Lange, P., Vessella, R., Lin, D., Hood, L., & Nelson, P. S. (2006). A molecular correlate to the Gleason grading system for prostate adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 103(29), 10991-10996. https://doi.org/10.1073/pnas.0603678103