Volume 72, Issue 5, Pages 665-674 (November 2017) A Prostate Cancer “Nimbosus”: Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies  Melvin L.K. Chua, Winnie Lo, Melania Pintilie, Jure Murgic, Emilie Lalonde, Vinayak Bhandari, Osman Mahamud, Anuradha Gopalan, Charlotte F. Kweldam, Geert J.L.H. van Leenders, Esther I. Verhoef, Agnes Marije Hoogland, Julie Livingstone, Alejandro Berlin, Alan Dal Pra, Alice Meng, Junyan Zhang, Michèle Orain, Valérie Picard, Hélène Hovington, Alain Bergeron, Louis Lacombe, Yves Fradet, Bernard Têtu, Victor E. Reuter, Neil Fleshner, Michael Fraser, Paul C. Boutros, Theodorus H. van der Kwast, Robert G. Bristow  European Urology  Volume 72, Issue 5, Pages 665-674 (November 2017) DOI: 10.1016/j.eururo.2017.04.034 Copyright © 2017 European Association of Urology Terms and Conditions

Fig. 1 Clinical outcomes stratified by intraductal carcinoma (IDC) and cribriform architecture (CA). Biochemical relapse-free rates for (A) Canadian, and (B) MSKCC cohorts. (C) Metastasis-free rates using pooled data. European Urology 2017 72, 665-674DOI: (10.1016/j.eururo.2017.04.034) Copyright © 2017 European Association of Urology Terms and Conditions

Fig. 2 Outline of study and interactions between subpathologies and percentage of genome alteration (PGA). (A) To test for “aggression” field defect in clonal intraductal carcinoma (IDC), cribriform architecture (CA), and adjacent glandular adenocarcinoma, we characterized the association between IDC/CA+ prostate tumors and known adverse indices, and their association with biochemical and metastatic relapses. (B) Box and whisker (first/third quartiles ± interquartile range) plots of PGA in IDC/CA+ and IDC/CA– tumors for the pooled (left), Canadian (middle), and MSKCC (right) cohorts. (C) Biochemical relapse- and metastasis-free rates based on combinatorial pathological and genomic stratification in 476 men with NCCN-defined low- to high-risk prostate cancer. CHUdeQ-UL cohort (n=54, with pathological and genomic data) was excluded from analyses of metastasis-free rate, as no metastasis event was recorded in this subset of cases. CHUdeQ-UL=CHU de Québec-Université Laval; HR=hazards ratio; MSKCC=Memorial Sloan Kettering Cancer Center; NCCN=National Comprehensive Cancer Network. European Urology 2017 72, 665-674DOI: (10.1016/j.eururo.2017.04.034) Copyright © 2017 European Association of Urology Terms and Conditions

Fig. 3 SChLAP1 is highly expressed in prostate cancers harboring intraductal carcinoma (IDC) and cribriform architecture (CA). (A) Volcano plot of mRNA abundance of 156 tumors (Canadian cohort) showing differential gene expression between IDC/CA+ and IDC/CA– prostate cancers. (B) Box and whisker (first/third quartiles±IQR) plot comparison of SChLAP1 mRNA abundance between the two groups. (C) Independent validation of SChLAP1 association with IDC/CA, using RNA-ISH (≥5 signals cutoff) on tissue microarray (EMC cohort). (D) Diffuse SChLAP1 RNA-ISH signals in CA subpathology (open arrow) and adjacent invasive adenocarcinoma (closed arrows) support a field defect. (E) Biochemical relapse-free rate of Canadian cohort stratified by combinatorial IDC/CA and SChLAP1 (upper tertile cutoff), showing worst outcome in SChLAP1+, IDC/CA+ subgroup. EMC=Erasmus Medical Center; FC=fold change; FDR=false discovery rate; IQR=interquartile range; RNA-ISH=RNA in situ hybridization. European Urology 2017 72, 665-674DOI: (10.1016/j.eururo.2017.04.034) Copyright © 2017 European Association of Urology Terms and Conditions

Fig. 4 A prostate cancer nimbosus that is associated with intraductal (IDC) and cribriform (CA) subpathologies. CA=cribriform architecture; IDC=intraductal carcinoma; PSA=prostate-specific antigen; RNA-ISH=RNA in situ hybridization. European Urology 2017 72, 665-674DOI: (10.1016/j.eururo.2017.04.034) Copyright © 2017 European Association of Urology Terms and Conditions