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

doi:10.1016/j.eururo.2017.04.034

A Prostate Cancer "Nimbosus": Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies

Eur Urol. 2017 Nov;72(5):665-674. doi: 10.1016/j.eururo.2017.04.034. Epub 2017 May 13.

Authors

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

Affiliations

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.

PMID: 28511883
DOI: 10.1016/j.eururo.2017.04.034

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 (HR_Canadian 2.17, p<0.001; HR_MSKCC 2.32, p=0.0035) and metastasis (HR_pooled 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.

Keywords: Cribriform architecture; Genomic instability; Hypoxia; Intraductal carcinoma; Prognosis; SChLAP1.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / genetics*
Adenocarcinoma / mortality
Adenocarcinoma / pathology
Adenocarcinoma / therapy
Biomarkers, Tumor / genetics*
Disease Progression
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Genomic Instability*
Humans
Kaplan-Meier Estimate
Male
Neoplasm Invasiveness
Netherlands
New York City
Ontario
Phenotype
Proportional Hazards Models
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / mortality
Prostatic Neoplasms / pathology
Prostatic Neoplasms / therapy
Quebec
RNA, Long Noncoding / genetics*
Risk Factors
Time Factors
Transcriptome
Treatment Outcome
Tumor Hypoxia

Substances

Biomarkers, Tumor
RNA, Long Noncoding
SChLAP1 long noncoding RNA

Grants and funding

CIHR/Canada