Melvin L K Chua1, Winnie Lo1, Melania Pintilie1, Jure Murgic1, Emilie Lalonde2, Vinayak Bhandari2, Osman Mahamud3, Anuradha Gopalan4, Charlotte F Kweldam5, Geert J L H van Leenders5, Esther I Verhoef5, Agnes Marije Hoogland5, Julie Livingstone6, Alejandro Berlin1, Alan Dal Pra1, Alice Meng1, Junyan Zhang1, Michèle Orain7, Valérie Picard7, Hélène Hovington7, Alain Bergeron7, Louis Lacombe7, Yves Fradet7, Bernard Têtu7, Victor E Reuter4, Neil Fleshner8, Michael Fraser1, Paul C Boutros9, Theodorus H van der Kwast10, Robert G Bristow11. 1. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada. 2. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. 3. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. 4. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands. 6. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada. 7. Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada. 8. Division of Urology, University Health Network, University of Toronto, Toronto, ON, Canada. 9. Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, ON, Canada. 10. Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands; Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: Theodorus.vanderKwast@uhn.ca. 11. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. Electronic address: Rob.Bristow@rmp.uhn.on.ca.
Abstract
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.
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.
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