Department of Urology, Urological Science Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Center for Prostate Cancer, National Cancer Center, Goyang, Republic of Korea.
Prostate Cancer Prostatic Dis. 2021 Dec;24(4):1080-1092. doi: 10.1038/s41391-021-00364-x. Epub 2021 Apr 26.
Transcriptomic landscape of prostate cancer (PCa) shows multidimensional variability, potentially arising from the cell-of-origin, reflected in serum markers, and most importantly related to drug sensitivities. For example, Aggressive Variant Prostate Cancer (AVPC) presents low PSA per tumor burden, and characterized by de novo resistance to androgen receptor signaling inhibitors (ARIs). Understanding PCa transcriptomic complexity can provide biological insight and therapeutic guidance. However, unsupervised clustering analysis is hindered by potential confounding factors such as stromal contamination and stress-related material degradation.
To focus on prostate epithelial cell-relevant heterogeneity, we defined 1,629 genes expressed by prostate epithelial cells by analyzing publicly available bulk and single- cell RNA sequencing data. Consensus clustering and CIBERSORT deconvolution were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma dataset served as a training set. The resulting clusters were analyzed in association with clinical, pathologic, and genomic characteristics and impact on survival. Serum markers PSA and PAP was analyzed to predict response to docetaxel chemotherapy in metastatic setting.
We identified two luminal subtypes and two aggressive variant subtypes of PCa: luminal A (Adipogenic/AR-active/PSA-high) (30.0%); luminal S (Secretory/PAP-high) (26.0%); AVPC-I (Immune-infiltrative) (14.7%), AVPC-M (Myc-active) (4.2%), and mixed (25.0%). AVPC-I and AVPC-M subtypes predicted to be resistant to ARI and have low PSA per tumor burden. Luminal A and AVPC-M predicted to be resistant to docetaxel and have high PSA/PAP Ratio. Metastatic PCa patients with high PSA/PAP ratio (>20) had significantly shorter progression-free survival than those with low ratio (≤20) following docetaxel chemotherapy.
We propose four prostate adenocarcinoma subtypes with distinct transcriptomic, genomic, and pathologic characteristics. PSA/PAP ratio in advanced cancer may aid in determining which patients would benefit from maximized androgen receptor inhibition or early use of antimicrotubule agents.
前列腺癌（PCa）的转录组景观显示出多维可变性，可能源于细胞起源，反映在血清标志物中，最重要的是与药物敏感性相关。例如，侵袭性变异型前列腺癌（AVPC）表现为每肿瘤负担的 PSA 低，并且特征为对雄激素受体信号抑制剂（ARIs）的新发耐药性。了解 PCa 转录组的复杂性可以提供生物学见解和治疗指导。然而，无监督聚类分析受到潜在混杂因素的阻碍，例如基质污染和应激相关物质降解。
为了关注前列腺上皮细胞相关的异质性，我们通过分析公开的批量和单细胞 RNA 测序数据，定义了 1629 个由前列腺上皮细胞表达的基因。共识聚类和 CIBERSORT 去卷积用于发现类和比例估计分析。癌症基因组图谱前列腺腺癌数据集作为训练集。分析结果聚类与临床、病理和基因组特征以及对生存的影响相关联。分析血清标志物 PSA 和 PAP 以预测转移性环境中对多西紫杉醇化疗的反应。
我们确定了两种 luminal 亚型和两种侵袭性变异亚型的 PCa：luminal A（脂肪生成/AR 活跃/PSA 高）（30.0%）；luminal S（分泌/PAP 高）（26.0%）；AVPC-I（免疫浸润）（14.7%），AVPC-M（Myc 活跃）（4.2%）和混合（25.0%）。AVPC-I 和 AVPC-M 预测对 ARI 耐药，并且每肿瘤负担的 PSA 低。Luminal A 和 AVPC-M 预测对多西紫杉醇耐药，并且 PSA/PAP 比值高。接受多西紫杉醇化疗后，转移性 PCa 患者中 PSA/PAP 比值（>20）较高的患者无进展生存期明显短于比值（≤20）较低的患者。
我们提出了具有不同转录组、基因组和病理特征的四种前列腺腺癌亚型。晚期癌症中的 PSA/PAP 比值可能有助于确定哪些患者将受益于最大程度的雄激素受体抑制或早期使用抗微管药物。
