Cancer - Prostate(구연) (E-125)

전립선 상피 세포 기원 전사체 분석을 통한 4가지 전립선암의 분자생물학적 아형 보고
연세의대 신촌세브란스병원 ¹비뇨의학교실, ²병리학교실
한현호¹, 조남훈², 최영득¹, 나군호¹, Christopher J. Logothetis³ and Filippo G. Giancotti⁴
Transcriptomic analysis of the landscape of prostate adenocarcinoma has shown multidimensional gene expression variabilities closely associated with clinical and pathologic characteristics. Understanding the complexity of cancer transcriptome can provide biological insight and therapeutic guidance. Our vision is to create an approach that each tumor assigned to a molecular subtype based on their gene expressions. However, it is difficult to analyze the whole transcriptome due to potential confounding factors such as stromal contamination and stress-related material degradation. Alternatively, we defined the prostate epithelial cell expressed genes from single cell transcriptome of the human prostate gland.
By analyzing bulk and single cell RNA sequencing data publicly available, we defined 1,500 genes expressed by prostate epithelial cells. Consensus clustering and DeconRNAseq were used for class discovery and proportion estimate analysis. The Cancer Genome Atlas Prostate Adenocarcinoma (TCGA-PRAD) dataset was used as a training set. The resulting clusters were analyzed in association with clinical, pathologic, genomic characteristics and impact on survival.
The TCGA-PRAD tumors could be classified into four subtypes – subtype A (35.6%), subtype B (30.3%), subtype C (9.0%), subtype D (16.1%) and mixed (9.0%). Subtype C and D were associated with advanced T/N stages, high Gleason grades and poor survival. Subtype A was characterized by lowest frequency of TMPRSS2-ERG fusion and high levels of KLK3 gene expression which encodes PSA. Subtype B showed highest ACPP gene expression encoding PAP (Prostatic Acid Phosphatase). Subtype C was characterized by frequent genetic alterations of TP53 (38%), PTEN (62%) and low AR (Androgen Receptor) activity. Subtype D exhibited high expressions of AR protein and activation of ER (Estrogen Receptor).
We provide four subtypes of prostate adenocarcinoma with distinct transcriptomic, genomic and pathologic characteristics. Two aggressive subtypes defined, one potentially insensitive to AR inhibition and the other sensitive. Our analysis provides a beginning step in understanding prostate cancer biology based their cell of origin or they mimic of. The subtypes will be further examined by validation in multiple prospective cohorts and serum/tissue markers.
keywords : Molecular Subtypes, Prostate Adenocarcinoma