Probes for LONG

Prostate cancers remain indolent in the majority of individuals but behave aggressively in a minority. The molecular basis for this clinical heterogeneity remains incompletely understood. Here we characterize a long noncoding RNA termed SChLAP1 (second chromosome locus associated with prostate-1; also called LINC00913) that is overexpressed in a subset of prostate cancers. SChLAP1 levels independently predict poor outcomes, including metastasis and prostate cancer-specific mortality. In vitro and in vivo gain-of-function and loss-of-function experiments indicate that SChLAP1 is critical for cancer cell invasiveness and metastasis. Mechanistically, SChLAP1 antagonizes the genome-wide localization and regulatory functions of the SWI/SNF chromatin-modifying complex. These results suggest that SChLAP1 contributes to the development of lethal cancer at least in part by antagonizing the tumor-suppressive functions of the SWI/SNF complex.

The long noncoding RNA SChLAP1 is overexpressed in a subset of prostate cancers (PCa), and high SChLAP1 expression by in situ hybridization (ISH) independently predicts biochemical recurrence after radical prostatectomy. Importantly, although biochemical recurrence is a significant clinical outcome, it is not a validated surrogate for PCa-related mortality. Thus, we evaluated the association between SChLAP1 expression and development of lethal PCa in a large cohort of American men with PCa and long-term follow-up. SChLAP1 ISH was performed on tissue microarrays containing representative formalin-fixed, paraffin-embedded PCa tissue from all patients and scored using a semiquantitative method (ISH score range 0-400). Hazard ratios (HRs) for the association between SChLAP1 expression and time to development of lethal PCa were estimated using multivariable Cox regression analysis. Of the 937 patients evaluated, 89 (9.5%) had high SChLAP1 expression (ISH score ≥100), which in patients treated with radical prostatectomy was strongly associated with development of lethal PCa independent of age, Gleason score, pathologic stage, and PTEN status (HR 2.2, 95% confidence interval 1.1-4.1). These results suggest that SChLAP1 may be a useful tissue-based biomarker for identifying PCa patients at higher risk of lethal progression.

PATIENT SUMMARY:
We examined expression of the RNA molecule SChLAP1 in a large group of prostate cancer patients with long-term follow-up and found that patients with high SChLAP1 expression had a significantly higher chance of developing lethal disease.

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.