Background: Intraductal carcinoma (IDC) and cribriform architecture (CA) represent unfavorable subpathologies in localized prostate cancer. We recently showed that IDC shares a clonal ancestry with the adjacent glandular adenocarcinoma.
Objective: We investigated for the co-occurrence of "aggression" factors, genomic instability and hypoxia, and performed gene expression profiling of these tumors.
Design, setting, and participants: A total of 1325 men were treated for localized prostate cancer from four academic institutions (University Health Network, CHU de Québec-Université Laval, Memorial Sloan Kettering Cancer Center [MSKCC], and Erasmus Medical Center). Pathological specimens were centrally reviewed. Gene copy number and expression, and intraprostatic oxygenation were assessed.
Outcome measurements and statistical analysis: IDC/CA was separately assessed for biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled for analyses on metastasis.
Results and limitation: Presence of IDC/CA independently predicted for increased risks of biochemical relapse (HRCanadian 2.17, p <0.001; HRMSKCC 2.32, p =0.0035) and metastasis (HRpooled 3.31, p <0.001). IDC/CA+ cancers were associated with an increased percentage of genome alteration (PGA [median] 7.2 vs 3.0, p <0.001), and hypoxia (64.0% vs 45.5%, p =0.17). Combinatorial genomic-pathological indices offered the strongest discrimination for metastasis (C-index 0.805 [clinical+IDC/CA+PGA] vs 0.786 [clinical+IDC/CA] vs 0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1, was the only gene expressed at >3-fold higher (p <0.0001) in IDC/CA+ than in IDC/CA- tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal. Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing.
Conclusions: The poor outcome associated with IDC and CA subpathologies is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a novel concept in IDC/CA+ prostate cancer, ". nimbosus" (gathering of stormy clouds, Latin), which manifests as increased metastatic capacity and lethality.
Patient summary: A constellation of unfavorable molecular characteristics co-occur with intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveillance and treatment intensification trials should be considered in this adverse subgroup. We posit a prostate cancer ". nimbosus" that is hallmarked by the constellation of genomic instability, SChLAP1 dysregulation, hypoxia, and intraductal-cribriform subpathologies. Patients harboring these prostate cancers should be closely monitored and are recommended intensified treatment against an increased risk of metastases.

Additional Metadata
Keywords Cribriform architecture, Genomic instability, Hypoxia, Intraductal carcinoma, Prognosis, SChLAP1
Persistent URL dx.doi.org/10.1016/j.eururo.2017.04.034, hdl.handle.net/1765/99831
Journal European Urology : Official Journal of the European Association of Urology
Citation
Chua, M.L.K. (Melvin L.K.), Lo, W. (Winnie), Pintilie, M, Murgic, J. (Jure), Lalonde, E. (Emilie), Bhandari, V. (Vinayak), … Bristow, R.G. (2017). A Prostate Cancer "Nimbosus": Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies. European Urology : Official Journal of the European Association of Urology. doi:10.1016/j.eururo.2017.04.034