Heterogeneity and chronology of 6q15 deletion and ERG-fusion in prostate cancer

Abstract

// Martina Kluth 1, * , David Meyer 1, * , Antje Krohn 1 , Fabian Freudenthaler 1 , Melanie Bauer 1 , Georg Salomon 2 , Hans Heinzer 2 , Uwe Michl 2 , Stefan Steurer 1 , Ronald Simon 1 , Guido Sauter 1 , Thorsten Schlomm 2, 3 , Sarah Minner 1 1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Prostate Cancer Center, Martini-Clinic, Hamburg, Germany 3 Department of Urology, Section for Translational Prostate Cancer Research at University Medical Center Hamburg-Eppendorf, Hamburg, Germany * These authors contributed equally to this work Correspondence to: Ronald Simon, e-mail: r.simon@uke.de Keywords: 6q deletion, prostate cancer, ERG, MAP3K7, heterogeneity Received: August 27, 2015      Accepted: November 22, 2015      Published: December 14, 2015 ABSTRACT Prostate cancer is notorious for its heterogeneity, which poses a problem for the applicability of diagnostic molecular markers. However, heterogeneity analysis can provide valuable information on the chronology in which molecular alterations arise. Here, we constructed a heterogeneity tissue microarray (TMA) comprising samples from 10 different tumor areas of 189 prostate cancers each in order to study the sequence of two frequent molecular alterations, i.e. 6q15 deletion and TMPRSS2:ERG fusion. Previous work shows a marked inverse relationship between these alterations, suggesting that presence of one of these alterations might impact development of the other. 6q15 deletion was analyzed by fluorescence in situ hybridization and ERG-expression by immunohistochemistry. Only 6.6% of 334 ERG-positive but 28.4% of 440 ERG-negative TMA spots showed 6q15 deletions ( p < 0.0001). A breakdown of these data to the level of tumor foci revealed 6q deletions in 138 tumor foci that were large enough to have at least 3 analyzable TMA spots. These included 42 tumor foci with homogeneous ERG positivity and 16 with homogeneous 6q15 deletions. Remarkably, six of the 42 homogeneously ERG -positive tumor foci (14.3%) harbored small 6q15-deleted areas, but none of the 34 6q15-deleted foci showed areas of ERG positivity ( p = 0.022). In conclusion, our data suggest that ERG -fusion can precede 6q15 deletion, but not vice versa. The complete absence of ERG-positive tumor areas in 6q15-deleted tumor foci further suggest that the functional consequences of 6q15 deletions may prevent the development of TMPRSS2:ERG fusions.