Characterization of 1577 Primary Prostate Cancers Reveals Novel Biological and Clinicopathologic Insights into Molecular Subtypes

Abstract

Background Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 over-expression. Clinical assessment may aid in disease stratification, complementing available prognostic tests. Objective To determine the analytical validity and clinicopatholgical associations of microarray-based molecular subtyping. Design, Setting and Participants We analyzed Affymetrix GeneChip expression profiles for 1,577 patients from eight radical prostatectomy (RP) cohorts, including 1,351 cases assessed using the Decipher prognostic assay (performed in a CLIA-certified laboratory). A microarray-based (m-) random forest ERG classification model was trained and validated. Outlier expression analysis was used to predict other mutually exclusive non-ERG ETS gene rearrangements (ETS+) or SPINK1 over-expression (SPINK1+). Outcome Measurements Associations with clinical features and outcomes by multivariable logistic regression analysis and receiver operating curves. Results and Limitations The m-ERG classifier showed 95% accuracy in an independent validation subset (n=155 samples). Across cohorts, 45%, 9%, 8% and 38% of PCa were classified as m-ERG+, m-ETS+, m-SPINK1+, and triple negative (m-ERG−/m-ETS−/m-SPINK1−), respectively. Gene expression profiling supports three underlying molecularly defined groups (m-ERG+, m-ETS+ and m-SPINK1+/triple negative). On multivariable analysis, m-ERG+ tumors were associated with lower preoperative serum PSA and Gleason scores, but enriched for extraprostatic extension (p<0.001). m-ETS+ tumors were associated with seminal vesicle invasion (p=0.01), while m-SPINK1+/triple negative tumors had higher Gleason scores and were more frequent in Black/African American patients (p<0.001). Clinical outcomes were not significantly different between subtypes. Conclusions A clinically available prognostic test (Decipher) can also assess PCa molecular subtypes, obviating the need for additional testing. Clinicopathological differences were found among subtypes based on global expression patterns.

Prostatic cancers: understanding their molecular pathology and the 2016 WHO classification

“…DNA methylation cluster 1 contained twice the number of hypermethylated loci in comparison with cluster 3, and the epigenetic patterns were substantially different from those of ETV1 - and ETV4 -rearranged cancers, which exhibit more heterogeneous methylation levels. This diversity among ETS -positive subtypes is consistent with results from previous studies that suggest substantial molecular and clinicopathological differences between ERG - and non- ERG ETS -rearranged cancers [82, 83]. SPOP - and FOXA1 -mutant subsets showed homogeneous epigenetic profiles.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…These transcriptomic classifications were later confirmed, refined (Ando, Suguro, Kobayashi, Seto, & Honda, 2003;Guedj et al, 2012;Hu et al, 2006;Loi et al, 2007;Mackay et al, 2011;Rosenwald et al, 2002;Sørlie et al, 2001), used in preclinical models to stratify clinical trials (Barton, Hawkes, Wotherspoon, & Cunningham, 2012), and inspired the discovery of clinically and biologically heterogeneous subgroups in many other malignancies, including colorectal cancer (Budinska et al, 2013;De Sousa E Melo et al, 2013;Marisa et al, 2013;Roepman et al, 2014;Sadanandam et al, 2013;Schlicker et al, 2012), renal cell carcinoma (Brannon et al, 2012(Brannon et al, , 2010, glioma (Nutt et al, 2003;Shai et al, 2003), liver (Boyault et al, 2007;Chiang et al, 2008;Hoshida et al, 2009;Lee et al, 2004), bladder (Biton et al, 2014), prostate (Tomlins et al, 2015), acute myeloid leukemia (de Jonge, Huls, & de Bont, 2011;Mrózek, Radmacher, Bloomfield, & Marcucci, 2009;Silva et al, 2009;Verhaak et al, 2009), and other cancers (Barlin et al, 2015;de Reyni es et al, 2014;Guo et al, 2015).…”

The expression profile and prognostic value of SPINK1 in initially diagnosed bone metastatic prostate cancer

“…In some studies [15,16], SPINK1 was considered as an activator of aggressiveness and was associated with poor biochemical failure in patients underwent radical prostatectomy. Whereas, results from recent studies with large-scale population showed that SPINK1 seemed to be not associated with adverse prognosis [17,18].…”