A prostate cancer "nimbosus'': Genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies Journal Article
| Authors: | Chua, M. L. K.; Lo, W.; Pintilie, M.; Murgic, J.; Lalonde, E.; Bhandari, V.; Mahamud, O.; Gopalan, A.; Kweldam, C. F.; van Leenders, G. J. L. H.; Verhoef, E. I.; Hoogland, A. M.; Livingstone, J.; Berlin, A.; Dal Pra, A.; Meng, A.; Zhang, J.; Orain, M.; Picard, V.; Hovington, H.; Bergeron, A.; Lacombe, L.; Fradet, Y.; Têtu, B.; Reuter, V. E.; Fleshner, N.; Fraser, M.; Boutros, P. C.; van der Kwast, T. H.; Bristow, R. G. |
| Article Title: | A prostate cancer "nimbosus'': Genomic instability and SChLAP1 dysregulation underpin aggression of intraductal and cribriform subpathologies |
| 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. 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. © 2017 European Association of Urology |
| Keywords: | major clinical study; recurrence risk; disease association; metastasis; gene expression; gene expression profiling; cohort analysis; risk assessment; prostate cancer; hypoxia; adverse outcome; messenger rna; prostatectomy; genomic instability; gene dosage; biochemical recurrence; intraductal carcinoma; oxygenation; tumor hypoxia; predictive value; clinical outcome; image guided radiotherapy; cancer prognosis; cribriform architecture; prognosis; human; male; priority journal; article; long untranslated rna; schlap1 |
| Journal Title: | European Urology |
| Volume: | 72 |
| Issue: | 5 |
| ISSN: | 0302-2838 |
| Publisher: | Elsevier Science, Inc. |
| Date Published: | 2017-11-01 |
| Start Page: | 665 |
| End Page: | 674 |
| Language: | English |
| DOI: | 10.1016/j.eururo.2017.04.034 |
| PROVIDER: | scopus |
| PUBMED: | 28511883 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2017 -- Source: Scopus |
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