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

Chua, Melvin L K; Lo, Winnie; Pintilie, Melania; Murgic, Jure; Lalonde, Emilie; Bhandari, Vinayak; Mahamud, Osman; Gopalan, Anuradha; Kweldam, Charlotte F; van Leenders, Geert J L H; Verhoef, Esther I; Hoogland, Agnes Marije; Livingstone, Julie; Berlin, Alejandro; Dal Pra, Alan; Meng, Alice; Zhang, Junyan; Orain, Michèle; Picard, Valérie; Hovington, Hélène; ... (2017). A Prostate Cancer "Nimbosus": Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies. European urology, 72(5), pp. 665-674. Elsevier 10.1016/j.eururo.2017.04.034

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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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