mRNA expression signature of gleason grade predicts lethal prostate cancer

Kathryn L. Penney, Jennifer A. Sinnott, Katja Fall, Yudi Pawitan, Yujin Hoshida, Peter Kraft, Jennifer R. Stark, Michelangelo Fiorentino, Sven Perner, Stephen Finn, Stefano Calza, Richard Flavin, Matthew L. Freedman, Sunita Setlur, Howard D. Sesso, Swen Olof Andersson, Neil Martin, Philip W. Kantoff, Jan Erik Johansson, Hans Olov AdamiMark A. Rubin, Massimo Loda, Todd R. Golub, Ove Andrén, Meir J. Stampfer, Lorelei A. Mucci

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

Purpose: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results: We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion: Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.

Original languageEnglish (US)
Pages (from-to)2391-2396
Number of pages6
JournalJournal of Clinical Oncology
Volume29
Issue number17
DOIs
StatePublished - Jun 10 2011
Externally publishedYes

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Prostatic Neoplasms
Messenger RNA
Neoplasms
Area Under Curve
Prostate
Watchful Waiting
Neoplasm Grading
Prostate-Specific Antigen
Transcriptome
Genes
Ligation
Complementary DNA
Physicians
Health
Medical Overuse
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Penney, K. L., Sinnott, J. A., Fall, K., Pawitan, Y., Hoshida, Y., Kraft, P., ... Mucci, L. A. (2011). mRNA expression signature of gleason grade predicts lethal prostate cancer. Journal of Clinical Oncology, 29(17), 2391-2396. https://doi.org/10.1200/JCO.2010.32.6421

mRNA expression signature of gleason grade predicts lethal prostate cancer. / Penney, Kathryn L.; Sinnott, Jennifer A.; Fall, Katja; Pawitan, Yudi; Hoshida, Yujin; Kraft, Peter; Stark, Jennifer R.; Fiorentino, Michelangelo; Perner, Sven; Finn, Stephen; Calza, Stefano; Flavin, Richard; Freedman, Matthew L.; Setlur, Sunita; Sesso, Howard D.; Andersson, Swen Olof; Martin, Neil; Kantoff, Philip W.; Johansson, Jan Erik; Adami, Hans Olov; Rubin, Mark A.; Loda, Massimo; Golub, Todd R.; Andrén, Ove; Stampfer, Meir J.; Mucci, Lorelei A.

In: Journal of Clinical Oncology, Vol. 29, No. 17, 10.06.2011, p. 2391-2396.

Research output: Contribution to journalArticle

Penney, KL, Sinnott, JA, Fall, K, Pawitan, Y, Hoshida, Y, Kraft, P, Stark, JR, Fiorentino, M, Perner, S, Finn, S, Calza, S, Flavin, R, Freedman, ML, Setlur, S, Sesso, HD, Andersson, SO, Martin, N, Kantoff, PW, Johansson, JE, Adami, HO, Rubin, MA, Loda, M, Golub, TR, Andrén, O, Stampfer, MJ & Mucci, LA 2011, 'mRNA expression signature of gleason grade predicts lethal prostate cancer', Journal of Clinical Oncology, vol. 29, no. 17, pp. 2391-2396. https://doi.org/10.1200/JCO.2010.32.6421
Penney, Kathryn L. ; Sinnott, Jennifer A. ; Fall, Katja ; Pawitan, Yudi ; Hoshida, Yujin ; Kraft, Peter ; Stark, Jennifer R. ; Fiorentino, Michelangelo ; Perner, Sven ; Finn, Stephen ; Calza, Stefano ; Flavin, Richard ; Freedman, Matthew L. ; Setlur, Sunita ; Sesso, Howard D. ; Andersson, Swen Olof ; Martin, Neil ; Kantoff, Philip W. ; Johansson, Jan Erik ; Adami, Hans Olov ; Rubin, Mark A. ; Loda, Massimo ; Golub, Todd R. ; Andrén, Ove ; Stampfer, Meir J. ; Mucci, Lorelei A. / mRNA expression signature of gleason grade predicts lethal prostate cancer. In: Journal of Clinical Oncology. 2011 ; Vol. 29, No. 17. pp. 2391-2396.
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T1 - mRNA expression signature of gleason grade predicts lethal prostate cancer

AU - Penney, Kathryn L.

AU - Sinnott, Jennifer A.

AU - Fall, Katja

AU - Pawitan, Yudi

AU - Hoshida, Yujin

AU - Kraft, Peter

AU - Stark, Jennifer R.

AU - Fiorentino, Michelangelo

AU - Perner, Sven

AU - Finn, Stephen

AU - Calza, Stefano

AU - Flavin, Richard

AU - Freedman, Matthew L.

AU - Setlur, Sunita

AU - Sesso, Howard D.

AU - Andersson, Swen Olof

AU - Martin, Neil

AU - Kantoff, Philip W.

AU - Johansson, Jan Erik

AU - Adami, Hans Olov

AU - Rubin, Mark A.

AU - Loda, Massimo

AU - Golub, Todd R.

AU - Andrén, Ove

AU - Stampfer, Meir J.

AU - Mucci, Lorelei A.

PY - 2011/6/10

Y1 - 2011/6/10

N2 - Purpose: Prostate-specific antigen screening has led to enormous overtreatment of prostate cancer because of the inability to distinguish potentially lethal disease at diagnosis. We reasoned that by identifying an mRNA signature of Gleason grade, the best predictor of prognosis, we could improve prediction of lethal disease among men with moderate Gleason 7 tumors, the most common grade, and the most indeterminate in terms of prognosis. Patients and Methods: Using the complementary DNA-mediated annealing, selection, extension, and ligation assay, we measured the mRNA expression of 6,100 genes in prostate tumor tissue in the Swedish Watchful Waiting cohort (n = 358) and Physicians' Health Study (PHS; n = 109). We developed an mRNA signature of Gleason grade comparing individuals with Gleason ≤ 6 to those with Gleason ≥ 8 tumors and applied the model among patients with Gleason 7 to discriminate lethal cases. Results: We built a 157-gene signature using the Swedish data that predicted Gleason with low misclassification (area under the curve [AUC] = 0.91); when this signature was tested in the PHS, the discriminatory ability remained high (AUC = 0.94). In men with Gleason 7 tumors, who were excluded from the model building, the signature significantly improved the prediction of lethal disease beyond knowing whether the Gleason score was 4 + 3 or 3 + 4 (P = .006). Conclusion: Our expression signature and the genes identified may improve our understanding of the de-differentiation process of prostate tumors. Additionally, the signature may have clinical applications among men with Gleason 7, by further estimating their risk of lethal prostate cancer and thereby guiding therapy decisions to improve outcomes and reduce overtreatment.

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