Harvard School of Public Health, Boston, Massachusetts.Harvard Medical School; Harvard Radiation Oncology Program; Channing Laboratory, Brigham and Women's Hospital; Dana-Farber Cancer Institute, Boston; The Broad Institute, Cambridge; MA; Uppsala University, Uppsala; Karolinska Institutet, Stockholm; Örebro University Hospital, Örebro, Sweden; Comprehensive Cancer Center, University Hospital of Tuebingen, Tuebingen, Germany; University of Brescia, Brescia, Italy; and Weill Cornell Medical College, New York, NY.
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.
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.
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).
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.
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. Are you the author?
Reference: J Clin Oncol. 2011 May 2. Epub ahead of print.