factors were excluded. All tests of statistical significance were 2-sided at 5% level of significance. Combined model development and application (Metastatic Assay and CAPRA-S) A combined model using Metastatic Assay dichotomized calls and CAPRA-S dichotomized into Low risk (CAPRA-S: 0-5) and High risk (CAPRA-S: 6-10) was assessed in the resection validation cohort independently against biochemical and metastatic endpoints using Cox regression analysis (Supplementary Methods). Subjects were classified risk’ given a combined model result Assay Negative/CAPRA-S low risk; ‘Low otherwise subjects were labelled Risk’ (i.e. samples that were classified as Assay ‘High Negative/CAPRA-S high risk, Assay Positive/CAPRA-S low risk or Assay Positive/CAPRA-S high risk). See Supplemental Methods for additional experimental detail. RESULTS Molecular Subtyping and Identification of a Metastatic-subgroup in the Discovery cohort We hypothesized a molecular subgroup of poor prognosis primary prostate cancers would be transcriptionally similar to metastatic disease. To identify this subgroup, we measured gene expression in primary prostate cancers, primary prostate cancers with known concomitant metastases, metastatic lymph node samples and histologically confirmed normal prostate tissue (Supplementary Table 2). Unsupervised hierarchical clustering identified two sample groups and two gene clusters (Figure 1A). Importantly, one of the molecular subgroups (C1) demonstrated significant enrichment for primary cancers with known concomitant metastatic disease
factors were excluded. All tests of statistical significance were 2-sided at 5% level of significance. Combined model development and application (Metastatic Assay and CAPRA-S) A combined model using Metastatic Assay dichotomized calls and CAPRA-S dichotomized into Low risk (CAPRA-S: 0-5) and High risk (CAPRA-S: 6-10) was assessed in the resection validation cohort independently against biochemical and metastatic endpoints using Cox regression analysis (Supplementary Methods). Subjects were classified ‘Low risk’ given a combined model result Assay Negative/CAPRA-S low risk; otherwise subjects were labelled ‘High Risk’ (i.e. samples that were classified as Assay Negative/CAPRA-S high risk, Assay Positive/CAPRA-S low risk or Assay Positive/CAPRA-S high risk). See Supplemental Methods for additional experimental detail. RESULTS Molecular Subtyping and Identification of a Metastatic-subgroup in the Discovery cohort We hypothesized a molecular subgroup of poor prognosis primary prostate cancers would be transcriptionally similar to metastatic disease. To identify this subgroup, we measured gene expression in primary prostate cancers, primary prostate cancers with known concomitant metastases, metastatic lymph node samples and histologically confirmed normal prostate tissue (Supplementary Table 2). Unsupervised hierarchical clustering identified two sample groups and two gene clusters (Figure 1A). Importantly, one of the molecular subgroups (C1) demonstrated significant enrichment for primary cancers with known concomitant metastatic disease
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