前列腺癌（PCa）是一种临床上异质性疾病。本研究旨在基于前列腺特定生物过程创建一种基于表达式的亚型分类模型。使用前瞻性收集的原发性前列腺肿瘤（训练，n = 32,000；评估，n = 68,547）的基因表达谱进行无监督机器学习，创建了一种基于基底细胞与上皮细胞表达模式和其他与PCa生物学相关的基因特征的前列腺亚型分类器（PSC）。在五个其他临床队列中探索亚型分子通路和临床特征。分群得到四个亚型：上皮分化型（LD）、上皮增殖型（LP）、基底免疫型（BI）和基底神经内分泌型（BN）。LP和LD肿瘤均具有更高的雄激素受体活性。LP肿瘤还具有更高的细胞增殖基因，MYC活性和相似的同源重组缺陷特征。BI肿瘤具有显著的γ干扰素活性和免疫组织化学中的免疫浸润。BN肿瘤的特点是低雄激素受体活性表达，低免疫浸润和用神经内分泌表达模式富集。具有LD肿瘤的患者具有较不侵袭性的肿瘤特征，并在手术后具有最长的转移时间。只有具有BI肿瘤的患者在手术后接受放疗时获益于转移时间（危险比[HR]，0.09；95% CI，0.01-0.71；n = 855）。在一项将有转移的PCa患者随机分组接受去势疗法或联合多西他赛的三期试验中（n = 108），只有具有LP肿瘤的患者从多西他赛中获得生存益处（HR，0.21；95% CI，0.09-0.51）。使用超过100,000个肿瘤的表达谱，开发出一种PSC，可以识别具有不同生物学和临床特征的四种亚型。前列腺癌的表现可以是缓慢的或侵袭性的，并且在对某些治疗的反应方式上存在差异。为了根据生物特征区分前列腺癌，我们使用了超过100,000个前列腺肿瘤的数据开发了一种新的RNA标识，这是同类中最大的数据集。该标识可以为患者和医生提供诊断肿瘤侵袭性和对待疗法的易感性的信息，以帮助个性化癌症管理。© 2023年Wiley Periodicals LLC代表美国癌症学会发表的《癌症》（Cancer）.

Prostate cancer (PCa) is a clinically heterogeneous disease. The creation of an expression-based subtyping model based on prostate-specific biological processes was sought.Unsupervised machine learning of gene expression profiles from prospectively collected primary prostate tumors (training, n = 32,000; evaluation, n = 68,547) was used to create a prostate subtyping classifier (PSC) based on basal versus luminal cell expression patterns and other gene signatures relevant to PCa biology. Subtype molecular pathways and clinical characteristics were explored in five other clinical cohorts.Clustering derived four subtypes: luminal differentiated (LD), luminal proliferating (LP), basal immune (BI), and basal neuroendocrine (BN). LP and LD tumors both had higher androgen receptor activity. LP tumors also had a higher expression of cell proliferation genes, MYC activity, and characteristics of homologous recombination deficiency. BI tumors possessed significant interferon γactivity and immune infiltration on immunohistochemistry. BN tumors were characterized by lower androgen receptor activity expression, lower immune infiltration, and enrichment with neuroendocrine expression patterns. Patients with LD tumors had less aggressive tumor characteristics and the longest time to metastasis after surgery. Only patients with BI tumors derived benefit from radiotherapy after surgery in terms of time to metastasis (hazard ratio [HR], 0.09; 95% CI, 0.01-0.71; n = 855). In a phase 3 trial that randomized patients with metastatic PCa to androgen deprivation with or without docetaxel (n = 108), only patients with LP tumors derived survival benefit from docetaxel (HR, 0.21; 95% CI, 0.09-0.51).With the use of expression profiles from over 100,000 tumors, a PSC was developed that identified four subtypes with distinct biological and clinical features.Prostate cancer can behave in an indolent or aggressive manner and vary in how it responds to certain treatments. To differentiate prostate cancer on the basis of biological features, we developed a novel RNA signature by using data from over 100,000 prostate tumors-the largest data set of its kind. This signature can inform patients and physicians on tumor aggressiveness and susceptibilities to treatments to help personalize cancer management.© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.