Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer

// Martina Kluth 1, * , Simon Jung 1, * , Omar Habib 1 , Mina Eshagzaiy 1 , Anna Heinl 1 , Nina Amschler 1 , Sawinee Masser 1 , Malte Mader 1 , Frederic Runte 1 , Philipp Barow 1 , Sohall Frogh 1 , Jazan Omari 1 , Christina Moller-Koop 1 , Claudia Hube-Magg 1 , Joachim Weischenfeldt 2 , Jan Korbel 2 , Stefan Steurer 1 , Till Krech 1 , Hartwig Huland 3 , Markus Graefen 3 , Sarah Minner 1 , Guido Sauter 1 , Thorsten Schlomm 3, 4 and Ronald Simon 1 1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 2 Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany 3 Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 4 Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany * These authors have contributed equally to this work Correspondence to: Ronald Simon, email: r.simon@uke.de Keywords: prostate cancer; deletion lengthening; 6q; 16q; tissue microarray Received: September 11, 2017     Accepted: September 16, 2017     Published: November 11, 2017 ABSTRACT Prostate cancer is characterized by recurrent deletions that can considerably vary in size. We hypothesized that large deletions develop from small deletions and that this “deletion lengthening” might have a “per se” carcinogenic role through a combinatorial effect of multiple down regulated genes. In vitro knockdown of 37 genes located inside the 6q12-q22 deletion region identified 4 genes with additive tumor suppressive effects, further supporting a role of the deletion size for cancer aggressiveness. Employing fluorescence in-situ hybridization analysis on prostate cancer tissue microarrays, we determined the deletion size at 6q and 16q in more than 3,000 tumors. 16q and 6q deletion length was strongly linked to poor clinical outcome and this effect was even stronger if the length of both deletions was combined. To study deletion lengthening in cancer progression we eventually analyzed the entire cancers from 317 patients for 6q and 16q deletion length heterogeneity and found that the deletion expanded within 50-60% of 6q and 16q deleted cancers. Taken together, these data suggest continuous “deletion lengthening” as a key mechanism for prostate cancer progression leading to parallel down regulation of genes with tumor suppressive properties, some of which act cooperatively.